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My primary research interest concerns factors involved in the pathogenesis of gastro-esophageal reflux disease (GERD) and its complications, such as Barrett's esophagus. Over the past decade I have explored the potential role of COX-2 expression and activity, prostaglandin and leukotriene production and cell proliferation in inducing and amplifying symptoms and disease evolution. Ongoing studies in the area of Barrett's metaplasia involve characterizing unique cell surface or intracellular molecular changes that occur in the early stages of metaplastic transformation and identification of environmental factors that predispose to esophageal metaplasia. In particular, I am interested in the role of acid and bile reflux in modifying cellular alterations and contributing to dysplasia and neoplasia. Furthermore, in clinical studies, I am investigating the role of 24-hour dual pH monitoring in the management of patients with reflux-like dyspepsia, esophagitis, and Barretts esophagus, and particularly the role of intensive proton pump inhibitor therapy in chemoprevention against esophageal adenocarcinoma. I have a very active clinical base of patients with Barretts esophagus in which advanced diagnostic (narrow band imaging, in vivo confocal microscopy, chromo-endoscopy) as well as therapeutic (endoscopic mucosal resection, radiofrequency ablation) modalities are prospectively explored and validated.

Abstract

Esophageal diseases, both benign and malignant, impose an increasing burden to global health. In the West, gastroesophageal reflux disease (GERD) and Barrett's esophagus are increasing in prevalence and impact. In the East, squamous esophageal cancer remains a large burden, but increasingly, precancerous lesions related to GERD are recognized. We review the various advanced endoscopic techniques that have been developed to improve the accuracy of endoscopic identification of esophageal disease. These techniques are designed to increase the sensitivity of detecting disease and high-risk lesions, enable targeted biopsies, decrease total number of biopsies and costs for surveillance, but also guide therapy in real-time. After proper clinical validation, the widespread use of these technologies will lead to improved outcomes, mostly in cancer prevention.

Abstract

Clinical trials of several new treatments for opioid-induced constipation (OIC), chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C) have focused on differences between subjects relieved of constipation with placebo and active treatment. Patients and clinicians however, are more interested in the probability these treatments provide actual relief of constipation and its associated symptoms.We searched the medical literature using MEDLINE and Cochrane central register of controlled trials. Randomised, placebo-controlled trials that examined the use of methylnaltrexone, naloxegol, lubiprostone, prucalopride or linaclotide in adults with OIC, CIC and IBS-C were eligible for inclusion. The primary efficacy measure was relief of constipation. Adverse event data for abdominal symptoms were also analysed.25 publications were included in our analyses. The proportion of constipated individuals with active treatment was significantly lower than the proportion with placebo; however, in 15 of these 20 trials analysed, a majority of patients remained constipated with active treatment. Analyses of adverse event data revealed that the percentage of participants who experienced abdominal pain, diarrhoea and flatulence with active treatment was higher than that with placebo in the majority of trials analysed.Newer pharmacological treatments for constipation are superior to placebo in relieving constipation, but many patients receiving active treatment may remain constipated. In addition, all 5 of the treatments studied are accompanied by no change or a possible increase in the prevalence of abdominal symptoms, such as abdominal pain, diarrhoea and flatulence.

Abstract

Little is known about differences in Barrett's esophagus (BE) characteristics by sex and race and/or ethnicity or these differences in response to radiofrequency ablation (RFA).We compared disease-specific characteristics, treatment efficacy, and safety outcomes by sex and race and/or ethnicity in patients treated with RFA for BE.The U.S. RFA patient registry is a multicenter collaboration reporting processes and outcomes of care for patients treated with RFA for BE.Patients enrolled with BE.RFA.We assessed safety (stricture, bleeding, perforation, hospitalization), efficacy (complete eradication of intestinal metaplasia [CEIM]), complete eradication of dysplasia, and number of treatments to CEIM by sex and race and/or ethnicity.Among 5521 patients (4052 men; 5126 white, 137 Hispanic, 82 African American, 40 Asian, 136 heritage not identified), women were younger (60.0 vs 62.1 years) and had shorter BE segments (3.2 vs 4.4 cm) and less dysplasia (37% vs 57%) than did men. Women were almost twice as likely to stricture (odds ratio 1.7; 95% confidence interval, 1.2-2.3). Although white patients were predominantly male, about half of African Americans and Asians with BE were female. African Americans and Asians had less dysplasia than white patients. Asians and African Americans had more strictures than did white patients. There were no sex or race differences in efficacy.Observational study with non-mandated paradigms, no central laboratory for reinterpretation of pathology.In the U.S. RFA patient registry, women had shorter BE segments and less-aggressive histology. The usual tendency toward BE in men was absent in African Americans and Asians. Posttreatment stricture was more common among women and Asians. RFA efficacy did not differ by sex or race.

Abstract

Endoscopic eradication therapy for dysplastic Barrett's esophagus (BE) comprises resection and mucosal ablation techniques. Over the years, these techniques have been tried with success, not only for dysplastic Barrett's epithelium but also for non-dysplastic Barrett's epithelium and early adenocarcinoma. Endoscopic resection is usually carried out for visible lesions, either as endoscopic mucosal resection (EMR), which is practiced widely in Western countries, or as endoscopic submucosal dissection, which is more popular in Japan and throughout Asia. Among ablative techniques are photodynamic therapy, cryotherapy, and radiofrequency ablation (RFA).We reviewed the published evidence pertaining to endoscopic treatments of dysplastic BE, with emphasis on the various resection and ablative techniques, their safety, efficacy, durability of effect, and tolerability.Both resection and ablation procedures performed endoscopically have been proved effective, and safe for treating dysplastic BE and early adenocarcinoma. Among the ablative techniques, RFA has shown to be more effective and safe, and is preferred for most cases.Endoscopic therapies have revolutionized the treatment of BE and have minimized the need for surgical intervention in many patients. Concomitant treatment of acid reflux with proton pump inhibitors and continuous surveillance are essential. Combination techniques such as EMR followed by RFA may be also considered in some cases.

Abstract

Gastroesophageal reflux disease (GERD) is a condition that develops when the reflux of stomach contents into the esophagus causes troublesome symptoms, esophageal injury, and/or complications. Use of proton pump inhibitors (PPI) remains the standard therapy for GERD and is effective in most patients. Those whose symptoms are refractory to PPIs should be evaluated further and other treatment options should be considered, according to individual patient characteristics. Response to PPIs could be total (no symptoms), partial (residual breakthrough symptoms), or absent (no change in symptoms). Patients experiencing complete response do not usually need further management. Patients with partial response can be treated surgically or by using emerging endoscopic therapies. Patients who exhibit no response to PPI need further evaluation to rule out other causes.

Abstract

Over the past two decades, there has been an increase in the number of anti-reflux operations being performed. This is mostly due to the use of laparoscopic techniques, the increasing prevalence of gastroesophageal reflux disease (GERD) in the population, and the increasing unwillingness of patients to take acid suppressive medications for life. Laparoscopic fundoplication is now widely available in both academic and community hospitals, has a limited length of stay and postoperative recovery time, and is associated with excellent outcomes in carefully selected patients. Although the operation has low mortality and postoperative morbidity, it is associated with late postoperative complications, such as gas bloat syndrome, dysphagia, diarrhea, and recurrent GERD symptoms. This review summarizes the diagnostic evaluation and appropriate management of such postoperative complications. If a reoperation is needed, it should be performed by experienced foregut surgeons.

Abstract

One potential option for the management of refractory gastro-esophageal reflux disease (GERD) is the delivery of radiofrequency energy to the gastro-esophageal junction (Stretta). This endoscopic therapy is safe, effective, durable, and repeatable if necessary and serves an unmet need for many GERD sufferers. Stretta could be effective in decreasing esophageal sensitivity to acid and in decreasing the gastro-esophageal junction compliance, which in turn contributes to symptomatic benefit by decreasing refluxate volume. Therefore, Stretta may serve as an endoscopic pain modulator and should be considered in patients with refractory symptoms despite proton pump inhibitors, as well as in patients with functional heartburn.

Abstract

Glucocorticoids are widely used as anti-inflammatory and immunosuppressive agents in many immune-mediated gastrointestinal diseases. However, a number of undesirable side effects may occur and dictate continuous surveillance and monitoring to prevent complications.This review of the English language literature identified on PubMed focuses on key aspects of glucocorticoid therapy in patients with gastrointestinal diseases, highlighting specific aspects of recognition and management of its secondary effects.Long-term cohort studies as well as placebo- and sham-controlled trials have evaluated the clinical efficacy, safety and tolerability of glucocorticoid therapy in many gastrointestinal diseases. Other immunosuppressive and biological therapies have made glucocorticoid therapy part of a broader arsenal of therapies. Newer compounds that carry less systemic toxicity and improved tolerability are increasingly used. For several gastrointestinal diseases, the role of the mucosal immunity is currently being explored and microscopic inflammation of the intestinal mucosa may have an important pathogenetic role. Glucocorticoid therapy, particularly with newer, safer compounds, may play an important new role in patients with altered motility and visceral hypersensitivity. The interplay of the gut microbiota and the host that contributes to the development of gut-associated lymphoid tissues and gut-specific immune responses will also undoubtedly be explored.

Abstract

There is a need to cleanse patients who are poorly prepared for colonoscopy safely and efficiently during the procedure to minimize rescheduling. US is already being used in catheter-based intravascular thrombolysis, and time-reversal acoustic (TRA) has been explored in assisting drug delivery to the brain.To explore the efficacy and safety of a miniaturized endoluminal US device in stool dissolution as a means to salvage poor bowel preparation.Proof of concept experimental study.Animal laboratory.Low-frequency US and TRAs.Feasibility, efficacy, and safety of US to liquefy stools ex vivo.Depending on parameters, such as pulse rate, acoustic intensity, and duration, increases in liquefaction speeds by a factor of 50 and 100 times were obtained. There was a significant difference in weight change between the 20-kHz-treated sample compared with controls (P ≤ .0001). There was no difference in sloughing of mucosa and mechanical injury among the US, water spray, and control groups.Animal model.Endoluminal US can liquefy stools at acoustic exposure levels that do not damage ex vivo colonic mucosa. Endoluminal US should be able to dissolve stools more rapidly than water spray alone, thereby optimizing colonoscopic evaluation in vivo.

Abstract

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the endoscopic tools to recognize squamous cell dysplasia; confocal laser endomicroscopy for Barrett's esophagus; confocal microscopy in the cancer patient; optical coherence tomography in the assessment of subsquamous Barrett's metaplasia; endoscopic mucosal resection for high-grade dysplasia in Barrett's esophagus; HALO in the treatment of squamous dysplasia; and the use of fluorescence in situ hybridization to detect dysplasia and adenocarcinoma in patients with Barrett's esophagus.

Abstract

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the role of salivary stimulation and esophageal secretion of protective factors in prevention of adenocarcinoma sequelae in gastroesophageal reflux disease; the pediatric conditions associated with esophageal cancer; the relationship of achalasia and pseudoachalasia with esophageal cancer; the potential for malignant transformation in eosinophilic esophagitis and overlap syndromes; the role of lymphocytic esophagitis as an overlapping phenotype; the role of Barrett's esophagus as a premalignant condition; the indications and type of treatment of premalignant conditions of the esophagus; and the decision for use of endoscopical procedures in premalignant conditions of the esophagus.

Abstract

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the animal reflux-inflammation models for Barrett's esophagus and esophageal adenocarcinoma; genomic/epigenomic analyses; eflornithine-based combinations; the molecular derangements that promote neoplastic transformation; the role of COX-2 inhibitors, proton pump inhibitors, and phase II trials in Barrett's adenocarcinoma; statins in chemoprevention and treatment of esophageal cancer; and biomarkers as potential targets in Barrett's adenocarcinoma.

Abstract

Postural orthostatic tachycardia syndrome (POTS) is a rare disease that is believed to be mediated by dysautonomia. Gastrointestinal complaints in POTS patients are common and disturbing but not well characterized.We hypothesized that gastrointestinal dysmotility may be contributory to these symptoms.We studied 12 POTS patients who presented with gastrointestinal symptoms to a tertiary referral center. Gastrointestinal symptoms were quantified using a previously validated symptom questionnaire. All patients underwent gastroduodenal manometry (GDM); select patients also underwent further testing including esophageal manometry (EM), anorectal manometry (ARM), plain abdominal radiography (AXR), abdominal computed tomography (CT), gastric emptying studies (GES), and colonic transit time (CTT) studies.The four most common symptoms were bloating, constipation, abdominal pain, and nausea/vomiting, all experienced by greater than 70 % of patients. On GDM testing, 93 % of patients demonstrated signs of neuropathy, and the most common abnormalities observed included bursts of uncoordinated phasic activity in both fasting (59 %) and post-prandial (42 %) states, low contractility in the post-prandial state (67 %), and lack of post-prandial pattern (42 %). A total of 67 % of patients undergoing EM and 86 % of those undergoing ARM demonstrated abnormalities consistent with dysmotility. On AXR or CT, 58 % demonstrated either dilated intestinal loops or air-fluid levels. On CTT 80 % demonstrated delayed colonic transit, while on GES 60 % demonstrated delayed gastric emptying.In this cohort of POTS patients with gastrointestinal symptoms, there is a high prevalence of abnormal manometric and radiographic findings suggestive of dysmotility.

Abstract

Barrett's esophagus (BE) is a well-established pre-malignant lesion for esophageal adenocarcinoma, a condition that carries a dismal five-year overall survival rate of less than 15%. Among several available methods to eliminate BE, radiofrequency ablation (RFA) provides the most efficient modality, since it has been demonstrated to successfully eradicate BE with or without dysplasia with acceptable safety, efficacy and durability profiles. In conjunction with proton pump therapy, this new technology has quickly become the standard care for patients with dysplastic BE. However, several technical questions remain about how to deploy RFA therapy for maximum effectiveness and long-term favorable outcomes for all stages of the disease. These include how to select patient for therapy, what the best protocol for RFA is, when to use other modalities, such as endoscopic mucosal resection, and what should be considered for refractory BE. This review addresses these questions with the perspective of the best available evidence matched with the authors' experience with the technology.

Abstract

Introduction: Although the exact prevalence of proton pump inhibitor (PPI) use in cancer patients is not known, it is generally perceived to be widespread. PPIs are generally well tolerated and carry an excellent safety profile. However, increasing and longer term PPI use has raised concerns about the risk of pneumonia, bone fractures and enteric infections, and a possible interaction with clopidogrel that could increase the risk of cardiovascular events. Areas covered: We conducted a PubMed search of English language articles addressing the safety and adverse events associated with PPI use with particular emphasis in cancer patients. Expert opinion: PPIs, frequently used in cancer patients, are generally well tolerated and carry an excellent safety profile. PPI-induced acid suppression may increase the risk of Clostridium difficile or other enteric infections, nutritional deficiencies and community acquired pneumonia, all particularly important in cancer patients. The indications for PPI use in cancer patients should be carefully reviewed prior to use.

Abstract

Patients with symptoms suggestive of gastroesophageal reflux disease (GERD), such as chest pain, heartburn, regurgitation, and dysphagia, are typically treated initially with a course of proton pump inhibitors (PPIs). The evaluation of patients who have either not responded at all or partially and inadequately responded to such therapy requires a more detailed history and may involve an endoscopy and esophageal biopsies, followed by esophageal manometry, ambulatory esophageal pH monitoring, and gastric emptying scanning. To assess the merits of a multimodality 'structural' and 'functional' assessment of the esophagus in patients who have inadequately controlled GERD symptoms despite using empiric PPI, a retrospective cohort study of patients without any response or with poor symptomatic control to empiric PPI (>2 months duration) who were referred to an Esophageal Studies Unit was conducted. Patients were studied using symptom questionnaires, endoscopy (+ or - for erosive disease, or Barrett's metaplasia) and multilevel esophageal biopsies (eosinophilia, metaplasia), esophageal motility (aperistalsis, dysmotility), 24-hour ambulatory esophageal pH monitoring (+ if % total time pH < 4 > 5%), and gastric emptying scanning (+ if >10% retention at 4 hours and >70% at 2 hours). Over 3 years, 275 patients (147 men and 128 women) aged 16-89 years underwent complete multimodality testing. Forty percent (n= 109) had nonerosive reflux disease (esophagogastroduodenoscopy [EGD]-, biopsy-, pH+); 19.3% (n= 53) had erosive esophagitis (EGD+); 5.5% (n= 15) Barrett's esophagus (EGD+, metaplasia+); 5.5% (n= 15) eosinophilic esophagitis (biopsy+); 2.5% (n= 7) had achalasia and 5.8% (n= 16) other dysmotility (motility+, pH-); 16% (n= 44) had functional heartburn (EGD-, pH-), and 5.8% (n= 16) had gastroparesis (gastric scan+). Cumulative symptom scores for chest pain, heartburn, regurgitation, and dysphagia were similar among the groups (mean range 1.1-1.35 on a 0-3 scale). Multimodality evaluation changed the diagnosis of GERD in 34.5% of cases and led to or guided alternative therapies in 42%. Overlap diagnoses were frequent: 10/15 (67%) of patients with eosinophilic esophagitis, 12/16 (75%) of patients with gastroparesis, and 11/23 (48%) of patients with achalasia or dysmotility had concomitant pathologic acid reflux by pH studies. Patients with persistent GERD symptoms despite empiric PPI therapy benefit from multimodality evaluation that may change the diagnosis and guide therapy in more than one third of such cases. Because symptoms are not specific and overlap diagnoses are frequent and multifaceted, objective evidence-driven therapies should be considered in such patients.

Abstract

Foreign body impaction in the esophagus is an important emergency that carries significant morbidity and potential mortality. The most common cause of esophageal foreign body obstruction in adults is meat bolus impaction above a pre-existing distal esophageal (mucosal) ring, peptic or malignant esophageal stricture, or eosinophilic esophagitis. Immediate evaluation of the airway, assessment of the urgency of removal, radiological evaluation to localize the object, endoscopic or surgical retrieval, and subsequent monitoring for complications are essential steps in the management.

Abstract

Ongoing gastroesophageal reflux may impair healing and re-epithelialization after radiofrequency ablation (RFA) of Barrett's esophagus (BE). Because prior fundoplication may improve reflux control, our aim was to assess the relationship between prior fundoplication and the safety/efficacy of RFA.We assessed the U.S. RFA Registry, a nationwide registry of BE patients receiving RFA at 148 institutions, to compare the safety and efficacy of ablation between those with prior fundoplication and those with medical management (proton pump inhibition).Among 5,537 patients receiving RFA, 301 (5.4 %) had prior fundoplication. Of fundoplication subjects, 1.0 % developed stricture and 1.0 % were hospitalized after RFA. Rates of stricture, bleeding, and hospitalization were not statistically different (p = ns) between patients with and without prior fundoplication. Complete eradication of intestinal metaplasia and complete eradication of dysplasia were achieved in 71 % and 87 % of fundoplication patients, and 73 % and 87 % of patients without fundoplication, respectively (p = ns for both). Patients with prior fundoplication needed similar numbers of RFA sessions for eradication compared with those without fundoplication.Radiofrequency ablation, with or without prior fundoplication, is safe and effective in eradicating BE. Prior fundoplication was associated with similar adverse event and efficacy rates when compared with medical management.

Abstract

Gastroesophageal reflux disease is one of the leading gastrointestinal disorders. Current treatments include lifestyle modifications, pharmacological therapies, surgical fundoplications, and, more recently, endoscopic procedures. The rising concern of long-term side effects of the popular proton-pump inhibitors and the more recent evidence raising doubts about the durability of fundoplication have spurred reinterest in endoscopic procedures to treat reflux disorders. In the aftermath of several innovative antireflux procedures that were introduced and failed clinically or financially over the past decade, there is lingering confusion regarding the merits of the presently available interventions. This paper focuses on one endoscopic procedure, Stretta, which now enjoys the longest experience, a recent meta-analysis, and robust data supporting its safety, efficacy, and durability. Stretta reduces esophageal acid exposure, decreases the frequency of transient lower esophageal relaxation, increases patient satisfaction, decreases medication use, and improves quality of life. As such, this procedure remains a valuable nonsurgical treatment option in the management of gastroesophageal reflux disease.

Abstract

Chronic constipation (CC) is a common condition but its concurrent conditions are not well characterized. We measured the prevalence and risk of developing 15 pre-specified concurrent conditions in patients with CC.Retrospective cohort study using the Medicaid database of California, utilizing ICD-9 codes for detection of cases (CC), controls (patients with GERD) and concurrent conditions. Study period was 01/01/1995 to 06/30/2005. Index date was the date 3 months before the first physician visit for CC. Pre-index time (12 months) was compared to post-index time (12 months) to assess the association of every concurrent condition within each cohort. To account for ascertainment bias, an adjusted odds ratio was calculated by comparing the odds ratio for every concurrent condition in the CC cohort to that in the GERD cohort.147,595 patients with CC (mean age 54.2 years; 69.7% women; 36.2% white) and 142,086 patients with GERD (mean age 56.3 years; 65.3% women; 41.6% white) were evaluated. The most prevalent concurrent conditions with CC were hemorrhoids (7.6%), diverticular disease (5.9%), ano-rectal hemorrhage (4.7%), irritable bowel syndrome (3.5%) and fecal impaction (2%). When adjusted for ascertainment bias, the most notable associations with CC were Hirschsprung's disease, fecal impaction and ano-rectal conditions such as fissure, fistula, hemorrhage and ulcers.Chronic constipation is associated with several concurrent conditions of variable risk and prevalence. To reduce the overall burden of CC, these concurrent conditions need to be addressed.

Abstract

Endoscopic radiofrequency ablation (RFA) is a promising new treatment of Barrett's esophagus (BE). Adjunctive intra-esophageal pH control with proton pump inhibitors and/or anti-reflux surgery is generally recommended to optimize squamous re-epithelialization after ablation.The aims of this study were to examine the association between intra-esophageal pH control and RFA outcomes and to identify predictive factors to achieve complete elimination (CE) of BE following RFA.We retrospectively studied the outcomes of BE patients treated with RFA. Esophageal acid exposure (EAE) was assessed utilizing 24-h pH monitoring on therapy. CE was endoscopically defined as no area suspicious for residual metaplasia following RFA.Of 45 patients (33 men; mean age 61.6, mean BE length C4.1 M4.6) examined for EAE, 29 % exhibited moderate-severe EAE despite therapy. Reduction in BE surface area and CE rate were higher in the normal-mild EAE group compared with the moderate-severe EAE group (99 vs. 95 %, p = 0.02; 44 vs. 15 %, p = 0.09, respectively). Using univariate analysis, age, gender, race, aspirin/NSAIDs use, baseline worst histology, baseline BE surface area, and the number or types of RFA had no correlation with CE. By multivariate multiple logistic regression analysis, normal-mild EAE and smaller hiatal hernia were independent factors associated with CE.Effective intra-esophageal pH control is associated with improved RFA outcomes of BE. Normal to mild EAE and smaller hiatal hernia are predictive factors to achieve CE. Given the frequent persistence of acid reflux despite therapy in BE patients, in order to maximize the RFA effects esophageal pH optimization and hernia repair should be considered.

Abstract

Esophageal achalasia is a primary esophageal motility disorder characterized by lack of peristalsis and a lower esophageal sphincter that fails to relax appropriately in response to swallowing. This article summarizes the most salient issues in the diagnosis and management of achalasia as discussed in a symposium that took place in Kagoshima, Japan, in September 2010 under the auspices of the International Society for Diseases of the Esophagus.

Abstract

Lower gastrointestinal bleeding, acute overt, occult or obscure in nature, causes significant morbidity and mortality in older adults. As the elderly population is expected to increase in the future, healthcare costs and the clinical burden of lower gastrointestinal bleeding will rise. Lower gastrointestinal bleeding, by definition, originates from a site distal to the ligament of Treitz and is usually suspected when patients present with haematochezia, or maroon stools per rectum. A thorough history is paramount in guiding the diagnostic steps and management but is frequently inadequate in elderly, poorly communicating, nursing home patients. The causes of lower gastrointestinal bleeding in older adults may be anatomic, vascular, inflammatory, neoplastic or iatrogenic. Comorbidity from cardiopulmonary disease, renal disease, diabetes or underlying cancer, all prevalent in older adults, may affect the incidence, severity, morbidity and mortality of lower gastrointestinal bleeding in the elderly. The use of multiple medications, particularly non-steroidal anti-inflammatory, antiplatelet and anticoagulant agents, needs to be always considered in elderly patients with lower gastrointestinal bleeding and anaemia. CT imaging and early colonoscopy are useful in determining the site of bleeding and allowing haemostasis. If unsuccessful, angiographic intervention and surgery need to be considered. Videocapsule endoscopy is useful in cases where the small bowel is suspected as the source, and its results guide the performance of double- or single-balloon enteroscopy. Optimal care should involve a coordinated effort among the primary physician, endoscopist, interventional radiologist and surgeon in order to improve prognosis and subsequent management and reduce morbidity, mortality, length of stay and overall healthcare costs.

Abstract

Reflux-like dyspepsia (RLD), where predominant epigastric pain is associated with heartburn and/or regurgitation, is a common clinical syndrome in both primary and specialty care. Because symptom frequency and severity vary, overlap among gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), and RLD, is quite common. The chronic and recurrent nature of RLD and its variable response to proton pump inhibitor (PPI) therapy remain problematic.To examine the prevalence of GERD, NERD, and RLD in a community setting using an algorithmic approach and to assess the potential, reproducibility, and validity of a multi-factorial scoring system in discriminating patients with RLD from those with GERD or NERD.Using a novel algorithmic approach, we evaluated an outpatient, community-based cohort referred to a gastroenterologist because of epigastric pain and heartburn that were only partially relieved by PPI. After an initial symptom evaluation (for epigastric pain, heartburn, regurgitation, dysphagia), an endoscopy and distal esophageal biopsies were performed, followed by esophageal motility and 24-h ambulatory pH monitoring to assess esophageal function and pathological acid exposure. A scoring system based on presence of symptoms and severity of findings was devised. Data was collected in two stages: subjects in the first stage were designated as the derivation cohort; subjects in the second stage were labeled the validation cohort.The total cohort comprised 159 patients (59 males, 100 females; mean age 52). On endoscopy, 30 patients (19%) had complicated esophagitis (CE) and 11 (7%) had Barrett's esophagus (BE) and were classified collectively as patients with GERD. One-hundred and eighteen (74%) patients had normal esophagus. Of these, 94 (59%) had one or more of the following: hiatal hernia, positive biopsy, abnormal pH, and/or abnormal motility studies and were classified as patients with NERD. The remaining 24 patients (15%) had normal functional studies and were classified as patients with RLD. Utilizing the scoring system a total score was calculated for each patient and effectively distinguished patients with GERD (mean score 9), NERD (mean score 6), and RLD (mean score 3). Receiver operating characteristic (ROC) curves confirmed the optimization of the model, particularly in RLD (P = 0.0001, 95% CI: 0.91-0.98).In a community cohort of patients presenting with heartburn and epigastric pain partly refractory to empiric PPI therapy, the prevalence of CE was 19%, BE 7%, NERD 59%, and RLD 15%. An algorithmic approach coupled with a novel scoring system, effectively distinguishes GERD from NERD and RLD and facilitates further management decisions. This novel and simple scoring system is both reproducible and validated as a diagnostic aid in evaluating patients presenting with both epigastric pain and heartburn.

Abstract

Current ablation devices for Barrett's esophagus are effective but have significant limitations.To evaluate a new ablation device.Laboratory and animal model evaluation of the CryoBalloon, a compliant balloon that is simultaneously inflated and cooled by liquid nitrous oxide delivered by using a small, disposable, handheld unit.Cryoablation of esophageal mucosa was performed in 11 swine. Multiple ablations were created in each animal at various ablation times.Animals were euthanized at 4 days (n = 6) or 28 days (n = 5), and histological assessments were performed. At 4 days, the percentage of esophageal mucosa successfully ablated was measured. At 28 days, the circumference of the esophagus at the center of the ablation zone was measured to assess for stricture formation.The CryoBalloon was simple to operate, and balloon contact with tissue was easily maintained. As the ablation time was increased from 6 to 12 seconds, the percentage of mucosa ablated increased from below 60% to above 90%. Maximal effect on the mucosa was reached at 12 seconds. Ablation of up to 14 seconds resulted in minimal luminal narrowing. As the ablation duration increased from 14 to 22 seconds, there was progressive stricture formation evident at 28 days. All of the animals tolerated the treatments without difficulty and, regardless of ablation duration, were able to continue oral intake and gain weight after the procedure.Ablation of normal porcine squamous mucosa may differ from that of human Barrett's esophagus.The CryoBalloon device enables circumferential mucosal ablation in a 1-step process by using a novel, through-the-scope balloon. The maximal effect on the mucosa is achieved with a 12-second application time. Because of its ease of use, this new device merits further study so that we can find its possible role in the treatment of Barrett's esophagus.

Abstract

Proton pump inhibitors have an excellent safety profile and have become one of the most commonly prescribed class of drugs in primary and specialty care. Long-term, sometimes lifetime, use is becoming increasingly common, often without appropriate indications. This paper is a detailed review of the current evidence on this important topic, focusing on the potential adverse effects of long-term proton pump inhibitor use that have generated the greatest concern: B12 deficiency; iron deficiency; hypomagnesemia; increased susceptibility to pneumonia, enteric infections, and fractures; hypergastrinemia and cancer; drug interactions; and birth defects. We explain the pathophysiological mechanisms that may underlie each of these relationships, review the existing evidence, and discuss implications for clinical management. The benefits of proton pump inhibitor use outweigh its risks in most patients. Elderly, malnourished, immune-compromised, chronically ill, and osteoporotic patients theoretically could be at increased risk from long-term therapy.

Abstract

Gastrointestinal illness may result from either an underlying structural abnormality (e.g. neoplastic obstruction), or a functional disorder (e.g. motor diarrhea), or both (e.g. achalasia with squamous esophageal cancer).The purpose of this study was to highlight the potential value and role of endoscopy in the recognition and management of patients with functional and motility disorders.We performed a literature review in PubMed.Diagnostic and therapeutic endoscopy may be under-used by motility-oriented gastroenterologists; in contrast, motility and other functional studies may be under-used by endoscopists. Yet, many areas of cross-exchange exist.This review aims to guide the appropriate indications for the use of endoscopy in diagnosing and treating functional GI and motility disorders and serve as a bridge and a forum of exchange between endoscopists and motility specialists.

Abstract

The following on surveillance and reversal of Barrett's esophagus (BE) includes commentaries on criteria for surveillance even when squamous epithelium stains normally with a variety of biomarkers; the long-term follow-up of surgery versus endoscopic ablation of BE; the recommended surveillance intervals in patients without dysplasia; the sampling problems related to anatomic changes following fundoplication; the value of tissue spectroscopy and optical coherence tomography; the cost-effectiveness of biopsy protocols for surveillance; the quality of life of Barrett's patients; and risk stratification and surveillance strategies.

Abstract

The following on progression to adenocarcinoma and markers of Barrett's esophagus includes commentariess on the expression of claudin 4 in Barrett's adenocarcinoma; the role of acid and bile salts; the role of insulin-like growth factor; the value of reactive oxygen species; the importance of abnormal methylation; genetic alterations in stromal cells and genomic changes in the epithelial cells; the value of confocal laser endomicroscopy for the subsurface analysis of the mucosa; indications for statins as adjuvant chemotherapeutic agent; the sequence of molecular events in malignant progression in Barrett's mucosa; and the value of the macroscopic markers and of p53 mutations.

Abstract

The following on proton pump inhibitors and chemoprevention in Barrett's esophagus includes commentaries on normalization of esophageal refluxate; the effects of 5-HT(4) agonists on EGF secretion and of lubripristone on chloride channels agents; the role of Campylobacter toxin production; the deleterious effects of unconjugated bile acids; the role of baclofen in nonacid reflux; the threshold for adequate esophageal acid exposure; the effects of proton pump inhibitor (PPI) therapy on normalization of esophageal pH and on cell proliferation; the role of the phenotype of cellular proliferation on the effects of PPI therapy; and the value of Symptom Index and Symptom Association Probability in the evaluation of potential response to treatment.

Abstract

The following includes commentaries on how genetic code of Barrett's esophagus (BE) patients, the mechanisms for GERD-induced esophageal expression of caudal homeobox, and the development of Barrett's metaplasia are increasingly better known, including the role of stromal genes in oncogenesis. Additional lessons have been learned in vitro models in nonneoplastic cell lines, yet there are limitations to what can be expected from BE-derived cell lines. Other topics discussed include clonal diversity in Barrett's esophagus; the application of peptide arrays to clinical samples of metaplastic mucosa; proliferation and apoptosis of Barrett's cell lines; tissue biomarkers for neoplasia; and transcription factors associated with BE.

Abstract

Barrett's esophagus (BE) is an important risk factor for esophageal carcinoma and its incidence is rising. Amongst the various available endoscopic ablative therapies, radiofrequency ablation (RFA) is currently regarded as the most promising one, since RFA achieves high eradication rates of dysplasia and intestinal metaplasia with minimal complications. Patients with BE are advised to undergo regular endoscopic surveillance for dysplasia or cancer and endoscopy with four quadrant biopsy sampling at intervals of 1-2 cm of the entire length of BE remains the current standard for the detection of dysplasia or cancer. The management of BE depends on the histology of the biopsy specimens obtained during endoscopy, which includes non-dysplastic BE (ND-BE), low grade dysplasia, high grade dysplasia and adenocarcinoma. However, histological evaluation of dysplasia is fraught with error because of inter-observer variability even among expert gastrointestinal pathologists, and as a result, it often leads to false-negative or false-positive diagnoses. Non-dysplastic mucosa in BE shows clonal molecular aberrations, loss of cell cycle control, and other features of "neoplasia". These changes occur prior to morphologic expression of neoplasia (dysplasia). Given the difficulties of dysplasia assessment in mucosal biopsies, the molecular characteristics of ND-BE and LGD, and safe and effective profiles of RFA, this technique should be considered as a treatment option for the whole spectrum of BE patients.

10th World Conference of the World Organization for Specialized Studies on Diseases of the Esophagus.Akiyama, J., Triadafilopoulos, G.2010: 697-699

Abstract

This meeting highlighted one individual topic, 'Barrett's esophagus', emphasizing unmet clinical needs in reflux disease, and focusing on many of the clinical challenges posted by 340 questions that were divided up among 17 plenary sessions, ten symposia, ten topic forums and six special sessions. Each presentation was concise, given in 5-10 min, and cast light on a highly focused aspect of the subject, followed by several minutes of lively discussion. This unique style of conference, characteristic of the World Organization for Specialized Studies on Diseases of the Esophagus, attracted a wide range of participants from all over the globe, and also provided opportunities to discuss the recent advances in the management of Barrett's esophagus.

Abstract

Non-dysplastic mucosa (ND-) in Barrett's esophagus (BE) shows clonal molecular aberrations, loss of cell cycle control, and other features of "neoplasia." These changes occur prior to morphologic expression of neoplasia (dysplasia). Morphologic evaluation of dysplasia is fraught with error, and, as a result, often leads to false-negative and false-positive diagnoses. Early "crypt dysplasia" is difficult to detect, and is often missed in routine biopsy specimens. Some studies show substantial progression rates of low-grade dysplasia (LGD), and crypt dysplasia, to esophageal adenocarcinoma (EAC). Dysplasia, even when fully developed, may, in certain circumstances, be difficult to differentiate from non-dysplastic (regenerating) BE. Radiofrequency ablation (RFA) is a safe and effective method for removing mucosa at risk of cancer. Given the difficulties of dysplasia assessment in mucosal biopsies, and the molecular characteristics of ND-BE, this technique should be considered for treatment of all BE patients, including those with ND or LGD. Post-ablation neo-squamous epithelium reveals no molecular abnormalities, and is biologically stable. Given that prospective randomized controlled trials of ablative therapy for ND-BE aiming at reducing EAC incidence and mortality are unlikely to be completed in the near future, endoscopic ablation is a valid management option. The success of RFA in achieving safe, uniform, reliable, and predictable elimination of BE allows surgeons to combine fundoplication with RFA. Currently, there is no type of treatment for dysplastic or non-dysplastic BE that achieves a complete response in 100% of patients, eliminates all risk of developing cancer, results in zero adverse events, is less expensive in terms of absolute costs than surveillance, is durable for 20+ years, or eliminates the need for surveillance. Regardless, RFA shows established safety, efficacy, durability, and cost-effective profiles that should be considered in the management of patients with non-dysplastic or low-grade dysplastic BE.

Abstract

Intestinal and extra-intestinal complications are associated with inflammatory bowel disease (IBD) but their exact incidence is not well known. In order to improve our understanding of their incidence and impact, we assessed the complications associated with ulcerative colitis (UC) and Crohn's disease (CD) in a population-based study in Medicaid patients.We utilized a retrospective cohort design and identified cases of UC and CD using Medi-Cal, the Medicaid program for the State of California. The disease cohort was age- and gender-matched to four controls each and the intestinal and extra-intestinal complications of CD and UC (analyzed separately) were studied over a period of 5 years following the initial diagnosis.For UC, the total number of intestinal complications, per 100 cases, was 92 observed compared to 21 expected; the total number of extra-intestinal complications was 42 observed compared to 30 expected. For CD, the number of intestinal complications was 81 observed compared to 20 expected and for extra-intestinal complications, 37 observed compared to 26 expected (all p < 0.001). For both UC and CD, bleeding was the most frequently seen intestinal complication, while the most common extra-intestinal complication was osteoporosis.IBD is associated with several intestinal and extra-intestinal complications of variable incidence and risk. Success of therapeutic regimens should be measured by decreases in incidence, risks, and costs of these complications, in addition to the usual impact on disease activity.

Abstract

A large controlled prospective observational study to compare pre- and postsurgery changes in reflux symptoms between cholecystectomy and hernia repair surgery patients.Six studies have suggested that gastroesophageal reflux worsens after cholecystectomy. However, all these studies had design limitations.We recruited 302 patients scheduled to undergo elective cholecystectomy (study group) or hernia repair (controls) at 2 hospitals. Both groups filled out the validated Reflux Symptom Score (RSS) and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires 1 to 15 days prior to and 4 to 12 weeks after the operation. Changes in symptom scores between the pre and postsurgery assessments were measured, and compared between the 2 groups.Baseline RSS and GSRS reflux subscores were higher in the study group than controls (1.44 vs. 1.02 and 1.91 vs. 1.43, respectively; P < 0.05). There were no significant differences in any of the symptom score changes between the 2 groups except for the GSRS pain subscore, which decreased more in the study group than the control group (-0.59 vs. -0.10; P < 0.001). With regard to reflux, the RSS decreased by -0.34 in the study group and -0.14 in controls (P = 0.27), while the GSRS reflux subscore decreased by -0.32 in the study group and -0.05 in controls (P = 0.12). GSRS diarrhea and constipation subscores decreased slightly after surgery, to the same extent in both groups.This large prospective controlled study, the only one using validated reflux symptom questionnaires, shows that cholecystectomy does not lead to an increase in reflux symptoms. As expected, GSRS pain subscores were decreased in the cholecystectomy group but not the controls.

Abstract

Distal esophageal or Schatzki's rings are a common cause of intermittent solid food dysphagia requiring endoscopic dilation for relief. Similarly, eosinophilic esophagitis (EE) is a rapidly emerging disease in both children and young adults, and manifests as dysphagia to solids and/or episodic food bolus impaction. Endoscopic findings vary considerably among patients with EE, posing significant recognition and management challenges. Esophageal dilation in EE can be painful and risky. This case report describes a patient with acute food bolus impaction due to underlying Schatzki's ring and associated but clinically indolent EE, and highlights some safety aspects of esophageal dilation.

What is left of the endoscopic antireflux devices?CURRENT OPINION IN GASTROENTEROLOGYJafri, S., Arora, G., Triadafilopoulos, G.2009; 25 (4): 352-357

Abstract

We critically analyze existing endoscopy-based interventions for gastroesophageal reflux disease (GERD). The focus is on the effectiveness of available procedures and to delineate goals for future research.Recent evaluations of the EndoCinch system reveal poor long-term results and no significant improvement over sham therapy due to poor apposition of mucosa with stitches. Recent studies with transoral incisionless fundoplication demonstrate improvement in GERD symptoms, quality of life, esophageal acid exposure, esophagitis, resting lower esophageal sphincter pressure and medication use. The SRS endoscopic stapling system creates a partial fundoplication wrap, and a preliminary study demonstrated improved symptoms and acid exposure. The Stretta system delivers radiofrequency energy to the gastroesophageal junction. A large prospective series demonstrates sustained improvement in GERD symptoms, quality of life and proton pump inhibitor therapy elimination after radiofrequency ablation at the gastroesophageal junction. A sham-controlled study showed improvement in symptoms at 6 months.EndoCinch plication requires further study and modification of technique before it can be recommended for general clinical use. Transoral incisionless fundoplication is a very promising procedure in its early stages of development. Further evaluation of procedure safety and durability is needed. Radiofrequency ablation therapy has been reintroduced and may have potential in patients with refractory GERD.

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are among the most commonly used medications worldwide. Their use is associated with significant gastroduodenal adverse effects, including dyspepsia, bleeding, ulcer formation, and perforation. Given their long-term use by millions of patients, there is a substantial impact at the population level of these complications. In this evidence-based review, we have endeavored to answer 12 commonly encountered questions in clinical practice that deal with the following: extent of the problem of NSAID/aspirin-induced gastroduodenal damage and its impact on public health; role of proton pump inhibitors (PPIs) in the primary prevention, healing, and secondary prevention of NSAID/aspirin-induced gastroduodenal ulceration as assessed by using endoscopic end points; role of PPIs in the prevention of adverse clinical outcomes related to NSAID/aspirin use; whether PPIs are effective in NSAID-induced dyspepsia; comparison of PPI co-therapy with selective cyclooxygenase-2 inhibitors for risk reduction of adverse clinical outcomes; role of PPIs in preventing rebleeding from aspirin +/- clopidogrel therapy in high-risk patients; identifying high-risk patients who can benefit from PPI co-therapy; the role of other gastroprotective agents for prevention of NSAID/aspirin-induced gastroduodenal damage; and the cost-effectiveness of and limitations to the use of PPIs for prevention of gastroduodenal damage related to the use of NSAIDs or aspirin. We then summarized our recommendations on the use of PPIs for the clinical management of patients using NSAIDs or aspirin.

Abstract

Previous studies that reported the incidence of perforation from a colonoscopy are limited by small sample sizes, restricted age groups, or single-center data.To determine the incidence and risk factors of colonic perforation from a colonoscopy in a large population cohort.Retrospective, population-based, cohort study, followed by a nested case-control study.California Medicaid program claims database.A total of 277,434 patients (aged 18 years and older) who underwent a colonoscopy during 1995 to 2005, age, sex, and time matched to 4 unique general-population controls.Perforation incidence in the 7 days after colonoscopy (or matched index date for controls) with odds ratio (OR); multivariate logistic regression to calculate adjusted ORs for subsequent analysis of risk factors.A total of 228 perforations were diagnosed after 277,434 colonoscopies, which corresponded to a cumulative 7-day incidence of 0.082%. The OR of getting a perforation from a colonoscopy compared with matched controls (n = 1,072,723) who did not undergo a colonoscopy was 27.6 (95% CI, 19.04-39.92), P < .001. On multivariate analysis, when comparing the group that had a perforation after a colonoscopy (n = 216) with those who did not (n = 269,496), increasing age, significant comorbidity, obstruction as an indication for the colonoscopy, and performance of invasive interventions during colonoscopy were significant positive predictors. Performance of biopsy or polypectomy did not affect the perforation risk. The rate of perforation did not change significantly over time.Validity of coding and capturing of all perforation diagnoses may possibly be deficient.The risk of perforation from a colonoscopy is low, but, despite increased experience with the procedure, it remains unchanged over time.

Abstract

Endoscopy can be used to monitor the onset of metaplastic transformation and to observe the progression of neoplasia in small animal models of Barrett's esophagus. By avoiding animal sacrifice, the natural history of this disease can be studied in a longitudinal fashion. We aim to characterize the endoscopic features of esophageal mucosa at various stages of the metaplasia-dysplasia-carcinoma sequence in a rat reflux model of Barrett's for comparison with histology. Acid and bile reflux was produced by introducing a side-to-side esophago-gastro-jejunostomy in Sprague-Dawley rats. Endoscopic examination of the distal esophagus was performed in 24 surgically altered and 4 control rats, between weeks 24 and 36 after the operation in 4-week intervals, and all rats were biopsied and sacrificed at 36 weeks. Endoscopic images were classified based on the surface mucosal patterns of the distal esophagus and then compared with histology. The endoscopic appearance was classified as: (i) normal, characterized by a smooth surface; (ii) intestinal metaplasia, defined as elevated plaques/ridges, deep grooves, and thin linear folds; (iii) dysplasia, indicated by coarse folds/grooves, meshlike villi, and foveolar appearance; and (iv) carcinoma, suggested by irregular-shaped mass lesions with ulcerations. The endoscopic criteria for intestinal metaplasia yielded a sensitivity of 100% in comparison with histology. Intestinal metaplasia with high-grade dysplasia was found in two rats and with low-grade dysplasia in three rats. Both focally invasive squamous cell carcinoma and invasive adenocarcinoma were found in one rat. Small animal endoscopy in a rat model of Barrett's esophagus can be used to perform surveillance, classify mucosal patterns, observe the onset of intestinal metaplasia, and monitor the progression of neoplastic transformation, representing a useful tool for studying the natural history of this disease.

Abstract

To determine the yield of colonoscopy in a predominantly Asian American gastroenterology practice in California from 8/2003 to 2/2005.A total 2,723 subjects were included: 87% were Asian and 13% were non-Asian. Advanced neoplasia prevalence was 12% in Asian men and 9% in non-Asian men (P = 0.21), and 8% and 7% in women (P = 0.62). Similar results were found in asymptomatic patients (13% and 13%, P = 0.99, for men; 8% and 6%, P = 0.46, for women). Factors associated with presence of advanced neoplasia were total number of polyps and presence of right-sided lesions. Asian men were more likely to have neoplasia overall compared with non-Asian men with odds ratio (OR) of 2.14 (1.23-3.72); however, there were no significant differences in the prevalences of advanced neoplasia in the two groups.Colorectal neoplasia is as prevalent in Asian Americans and preventive guidelines for colorectal cancer should also be advocated for this ethnic group.

Abstract

This invited profile summarizes the technical aspects and clinical trial results related to the use of circumferential and focal radiofrequency ablation in the management algorithm for Barrett's esophagus. What makes this relatively new endoscopic intervention unique is its promising safety and efficacy profile reported in published clinical trials. This technology appears to have overcome many of the limitations of prior endoscopic ablative modalities, and is thus garnering a role in the management of this disease state.

OUTCOMES AND RESOURCE UTILIZATION DURING HOSPITALIZATION FOR LIVER TRANSPLANTATION IN THE UNITED STATES AND THE IMPACT OF MELD: A NATIONWIDE STUDYArora, G., Vadhavkar, S., Singh, G., Friedman, G. D., Triadafilopoulos, G.WILEY-BLACKWELL.2008: 554A-555A

Abstract

To determine the proportion of Barrett's esophagus (BE) in Asians versus non-Asians and the predictors of BE in patients with upper gastrointestinal (GI) symptoms.We performed a cross-sectional study to determine the proportion of BE from all consecutive patients who underwent esophagogastroduodenoscopy (EGD) for various indications at an outpatient, community-based gastroenterology practice in northern California from February 2000 to September 2006. BE was defined as endoscopically recognized presence of salmon-pink mucosa in the distal esophagus and intestinal metaplasia on biopsy. We also performed a nested case-control study to determine potential predictors of BE.In total, 5,293 patients were reviewed. BE was more common in non-Asians (31/1464, 2.1%) than Asians (29/3829, 0.76%) (P < 0.001). In multivariate analysis controlling for increasing age, male gender, ethnicity, smoking, and alcohol, the strongest predictor of the presence of BE was non-Asian ethnicity (odds ratio [OR] 3.55, 95% confidence interval [CI] 1.85-6.85), followed by male gender (OR 2.68, 95% CI 1.32-5.45).BE is uncommon in Asian Americans; non-Asian ethnicity and male gender are significant independent predictors of BE.

Abstract

The management strategies for Barrett's esophagus (BE) that contains high-grade dysplasia (HGD) include intensive endoscopic surveillance, photodynamic therapy, thermal ablation, EMR, and esophagectomy.To assess the safety and effectiveness of endoscopic circumferential balloon-based ablation by using radiofrequency energy for treating BE HGD.Multicenter U.S. registry.Sixteen academic and community centers; treatment period from September 2004 to March 2007.Patients with histologic evidence of intestinal metaplasia (IM) that contained HGD confirmed by at least 2 expert pathologists. A prior EMR was permitted, provided that residual HGD remained in the BE region for ablation.Endoscopic circumferential ablation with follow-up esophageal biopsies to assess the histologic response to treatment.Histologic complete response (CR) end points: (1) all biopsy specimen fragments obtained at the last biopsy session were negative for HGD (CR-HGD), (2) all biopsy specimens were negative for any dysplasia (CR-D), and (3) all biopsy specimens were negative for IM (CR-IM).A total of 142 patients (median age 66 years, interquartile range [IQR] 59-75 years) who had BE HGD (median length 6 cm, IQR 3-8 cm) underwent circumferential ablation (median 1 session, IQR 1-2). No serious adverse events were reported. There was 1 asymptomatic stricture and no buried glands. Ninety-two patients had at least 1 follow-up biopsy session (median follow-up 12 months, IQR 8-15 months). A CR-HGD was achieved in 90.2% of patients, CR-D in 80.4%, and CR-IM in 54.3%.A nonrandomized study design, without a control arm, a lack of centralized pathology review, ablation and biopsy technique not standardized, and a relatively short-term follow-up.Endoscopic circumferential ablation is a promising modality for the treatment of BE that contains HGD. In this multicenter registry, the intervention safely achieved a CR for HGD in 90.2% of patients at a median of 12 months of follow-up.

A pilot study to assess the safety and efficacy of the Third Eye Retrograde auxiliary imaging system during colonoscopyENDOSCOPYTriadafilopoulos, G., Li, J.2008; 40 (6): 478-482

Abstract

Routine colorectal cancer screening, utilizing optical colonoscopy, has been shown to reduce the incidence and mortality rate of colorectal cancer. Despite its prevalence as the "gold standard" for neoplasia detection, the quality of colonoscopy screening is hindered by missed, undiagnosed lesions that may go undetected when located on the proximal aspect of haustral folds, rectal valves, the ileocecal valve, and/or flexures. The aim of this phase I feasibility trial is to assess the safety and efficacy of a new retrograde auxiliary imaging device, Third Eye Retroscope (Avantis Medical Systems, Inc., Sunnyvale, California, USA), used with optical colonoscopy to improve diagnostic yield.A total of 29 consecutive patients were enrolled in this phase I single-institution prospective series. Primary efficacy endpoint was identification of polyps in the retrograde image that were not identified in the antegrade image during colonoscope withdrawal.Of the 29 patients enrolled, 24 patients were treated and 34 out of a total of 38 polyps (classified as either adenoma or hyperplasia) were identified in the antegrade image. An additional four polyps, three hyperplastic and one adenoma, were identified in the retrograde image, and were detected on the proximal aspect of haustral folds during the colonoscope withdrawal, resulting in an 11.8% increase in diagnostic yield. No adverse events were encountered during the study.A retrograde auxiliary imaging device used in conjunction with a standard optical colonoscope proved to be safe, technically feasible, and clinically promising. A phase II multi-institutional study is currently underway to further evaluate this device.

Abstract

A Stanford University study reported that in asymptomatic GERD patients who were being treated with a proton pump inhibitor (PPI), 50% had pathologic esophageal acid exposure.We considered the possibility that the high prevalence of pathologic esophageal reflux might simply have resulted from calculating acidity as time pH < 4.We calculated integrated acidity and time pH < 4 from the 49 recordings of 24-hour gastric and esophageal pH from the Stanford study as well as from another study of 57 GERD subjects, 26 of whom were treated for 8 days with 20 mg omeprazole or 20 mg rabeprazole in a 2-way crossover fashion.The prevalence of pathologic 24-hour esophageal reflux in both studies was significantly higher when measured as time pH < 4 than when measured as integrated acidity. This difference was entirely attributable to a difference between the two measures during the nocturnal period. Nocturnal gastric acid breakthrough was not a useful predictor of pathologic nocturnal esophageal reflux.In GERD subjects treated with a PPI, measuring time esophageal pH < 4 will significantly overestimate the prevalence of pathologic esophageal acid exposure over 24 hours and during the nocturnal period.

Abstract

The junction between the esophagus and the stomach is a specialized region, composed of lower esophageal sphincter (LES) and its adjacent anatomical structures, the gastric sling and crural diaphragm. Together these structures work in a coordinated manner to allow ingested food into the stomach while preventing reflux of gastric contents across the esophago-gastric junction (EGJ) into the esophagus. The same zone also permits retrograde passage of air and gastric contents into esophagus during belching and vomiting. The precise coordination required to execute such a complicated task is achieved by a finely-regulated high-pressure zone. This zone keeps the junction between esophagus and stomach continuously closed, but is still able to relax briefly via input from inhibitory neurons that are responsible for its innervation. Alterations of the structure and function of the EGJ and the LES may predispose to gastroesophageal reflux disease (GERD).

Abstract

Proton Pump Inhibitors (PPIs) are widely used in the treatment of acid-peptic diseases. Their mechanism of action involves inhibition of the H-K-adenosine triphosphatase enzyme present in the parietal cells of the gastric mucosa. Because PPIs are the most potent inhibitors of gastric acid secretion available, they effectively alleviate acid-peptic symptoms and facilitate healing of inflamed or ulcerated mucosa. Although the use of PPIs is nowadays short term in patients with Helicobacter pylori-related peptic ulcer disease, these drugs are increasingly used long term, frequently for a lifetime, in patients with typical or atypical symptoms of gastro-oesophageal reflux disease, and in NSAID or aspirin users at risk for gastrotoxicity and related complications, such as bleeding, perforation and gastric outlet obstruction. This review outlines the essentials of PPI pharmacology, the safety and adverse profiles of the various available agents, and balances them against their clinical short- and long-term benefits. PPI use, prophylactically or with a therapeutic intent may also be combined with other strategies, such as endoscopic therapy, surgery or antibacterial use. Various clinical endpoints, such as symptom relief, mucosal healing, prevention of disease recurrence or complications, and cancer chemoprevention, are discussed and unmet needs are highlighted.

Abstract

Barrett's esophagus (BE) may be an adaptive cellular response to repeated acid exposure. The aims of this study were to compare intracellular acid loading in BE cells with normal squamous esophageal cells. Primary squamous and BE cells were obtained endoscopically and cultured for up to 24 h. Barrett's adenocarcinoma cell lines TE7 and OE-33 were compared with a normal esophageal (NE) cell line OE-21. Extracellular pH was lowered to 6.0 using HCl; specific ion exchangers were blocked pharmacologically and pH microfluorimetry was performed using 2'7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. The effect of prolonged acid preincubations and repeated acid exposure on acid loading and recovery were examined. Acid loading was greater in primary BE than NE cells (DeltapHi -0.22 +/- 0.08 vs.-0.13 +/- 0.01) and maximal in the BE carcinoma cell line TE7 (DeltapHi -0.30 +/- 0.01). Whereas TE7 cells were able to recover fully from repeated acid exposure, OE-21 cells remained profoundly acidic. BE primary and transformed cells utilize DIDS inhibitable sodium-independent chloride/bicarbonate exchange as well as sodium/hydrogen ion exchange for acid loading. In contrast, SE only requires sodium-independent chloride/bicarbonate exchange for acidification. The degree of acid loading is greater in BE than NE cells and it occurs via dual ion exchangers similar to gastric mucosa. Only Barrett's epithelial cells can maintain a physiological pHi following prolonged and repeated reflux exposure, which may confer a teleological advantage.

Abstract

Radiofrequency (RF) ablation using the HALO(360) system combined with proton pump inhibitor (PPI) therapy is a new treatment for Barrett's esophagus (BE). We assessed the safety and effectiveness of this combination therapy at a community-based, BE referral center. After symptom evaluation, endoscopy and histologic assessment, esophageal motility, pH monitoring on PPI, computed tomography, endoscopic ultrasonography and mucosal resection for nodules, we performed HALO(360) ablation followed by twice daily PPI and 3-monthly surveillance for up to 12 months. If metaplasia or dysplasia were present at follow-up, the patients received a second ablation. Thirteen patients (12 male) were treated, three with high-grade dysplasia, four with low-grade and six with non-dysplastic intestinal metaplasia. The mean baseline BE length was 6 cm (range 2-12); nine patients had an hiatal hernia and two had a prior fundoplication. Esophageal pH < 4.0 for < 4% of time was achieved only in 5/13 patients. A mean of 1.4 ablation sessions were performed, without serious adverse events or strictures. Complete eradication of BE was achieved in 6/13 (46%) patients. The mean endoscopic surface regression was 84% (from a mean length of 6 +/- 1 cm to 1.2 +/- 0.5 cm, P < 0.001). Complete elimination of dysplasia was achieved in 5/7 (71%) patients. Ablation efficacy was better in those patients who had maximal pH control (P < 0.05). HALO(360) ablation of BE with or without dysplasia is safe, well-tolerated and effective in the community setting. Follow-up ablation further reverses residual BE or dysplasia.

Abstract

Fourier transform infrared (FTIR) spectroscopy provides a unique molecular fingerprint of tissue from endogenous sources of light absorption; however, specific molecular components of the overall FTIR signature of precancer have not been characterized. In attenuated total reflectance mode, infrared light penetrates only a few microns of the tissue surface, and the influence of water on the spectra can be minimized, allowing for the analyses of the molecular composition of tissues. Here, spectra were collected from 98 excised specimens of the distal esophagus, including 38 squamous, 38 intestinal metaplasia (Barrett's), and 22 gastric, obtained endoscopically from 32 patients. We show that DNA, protein, glycogen, and glycoprotein comprise the principal sources of infrared absorption in the 950- to 1,800-cm(-1) regime. The concentrations of these biomolecules can be quantified by using a partial least-squares fit and used to classify disease states with high sensitivity, specificity, and accuracy. Moreover, use of FTIR to detect premalignant (dysplastic) mucosa results in a sensitivity, specificity, positive predictive value, and total accuracy of 92%, 80%, 92%, and 89%, respectively, and leads to a better interobserver agreement between two gastrointestinal pathologists for dysplasia (kappa = 0.72) versus histology alone (kappa = 0.52). Here, we demonstrate that the concentration of specific biomolecules can be determined from the FTIR spectra collected in attenuated total reflectance mode and can be used for predicting the underlying histopathology, which will contribute to the early detection and rapid staging of many diseases.

Abstract

The clinical significance of the trophic effects of long-term proton pump inhibitors (PPI)-related hypergastrinemia on colon polyps remains unknown.To study the frequency, growth, and histology of colon polyps in patients on chronic PPI therapy (cases), compared to those not receiving acid suppression (controls).Medical records of 2868 consecutive patients who underwent two or more colonoscopies, performed 3 or more months apart were reviewed. Cases (116) that used PPIs between the two colonoscopies were then compared to controls (194).Demographics and risk factors for colon cancer were comparable between the two groups. At baseline the mean frequency and size of adenomatous polyps were similar in cases and controls (P > 0.05) and at follow-up, these were 0.89 and 1.18 (P > 0.05; 95% CI of -0.08 to 0.66) and 4.09 mm and 4.00 mm (P > 0.05; 95% CI -2.29 to 2.11), respectively with no significant change. However, control group had a higher mean frequency and size of hyperplastic polyps at baseline as well as at follow-up colonoscopy (P < 0.05).The long-term use of PPI does not influence the frequency, growth, or histology of adenomatous polyps, but is associated with a reduction in both baseline and interval development of hyperplastic polyps.

Abstract

Outcomes of colon surveillance after colorectal cancer screening with colonoscopy are uncertain. We conducted a prospective study to measure incidence of advanced neoplasia in patients within 5.5 years of screening colonoscopy.Three thousand one hundred twenty-one asymptomatic subjects, age 50 to 75 years, had screening colonoscopy between 1994 and 1997 in the Department of Veterans Affairs. One thousand one hundred seventy-one subjects with neoplasia and 501 neoplasia-free controls were assigned to colonoscopic surveillance over 5 years. Cohorts were defined by baseline findings. Relative risks for advanced neoplasia within 5.5 years were calculated. Advanced neoplasia was defined as tubular adenoma greater than > or =10 mm, adenoma with villous histology, adenoma with high-grade dysplasia, or invasive cancer.Eight hundred ninety-five (76.4%) patients with neoplasia and 298 subjects (59.5%) without neoplasia at baseline had colonoscopy within 5.5 years; 2.4% of patients with no neoplasia had interval advanced neoplasia. The relative risk in patients with baseline neoplasia was 1.92 (95% CI: 0.83-4.42) with 1 or 2 tubular adenomas <10 mm, 5.01 (95% CI: 2.10-11.96) with 3 or more tubular adenomas <10 mm, 6.40 (95% CI: 2.74-14.94) with tubular adenoma > or =10 mm, 6.05 (95% CI: 2.48-14.71) for villous adenoma, and 6.87 (95% CI: 2.61-18.07) for adenoma with high-grade dysplasia.There is a strong association between results of baseline screening colonoscopy and rate of serious incident lesions during 5.5 years of surveillance. Patients with 1 or 2 tubular adenomas less than 10 mm represent a low-risk group compared with other patients with colon neoplasia.

Abstract

Constipation is a multisymptom disorder that frequently compromises quality of life and leads patients to seek medical advice. To evaluate the clinical and fiscal effects of constipation, we assessed health care resource use by patients with constipation enrolled in a large state Medicaid program.We identified 105,130 patients older than age 18 who saw a physician at least once for constipation and were enrolled in the California Medicaid program (Medi-Cal). We then studied health care resource use and costs (reimbursed by Medi-Cal) in 76,854 patients without supplementary insurance. The 15-month analysis period encompassed 3 months before and 12 months after the first visit. The prevalence of comorbid conditions was assessed in the sample of 105,130 patients.During the study period, 106,555 physician visits were for constipation; the total associated cost was $3,016,017 ($39/patient). The total cost for gastrointestinal procedures and laboratory testing was $14,052,503 ($183/patient). There were 41,723 over-the-counter and 1665 prescription drug purchases; the total cost was $388,780 ($5/patient). Approximately 0.6% of patients (n = 479) were admitted to the hospital for constipation; the total cost was $1,433,708 ($2993/admission). The total direct health care costs for patients with constipation in the Medi-Cal system for the 15-month period was $18,891,008 ($246/patient). Within 12 months of the first physician visit for constipation, 5657 of 105,130 patients had hemorrhoids and 2288 had intestinal impaction or obstruction.Adults seeking treatment for constipation account for significant health care resource use and often have comorbid conditions. The clinical and fiscal burden of constipation in US adults cannot be disregarded or trivialized.

Abstract

Today, there are several modalities to treat gastroesophageal reflux disease (GERD) (medications, endoscopic therapies, surgery) and such therapies can be used either singly, or in tandem, or in combination with the others, aiming at "normalization" of the patient's GERD-related quality of life and, if possible, esophageal acid exposure. Several intermediate end points or clinically significant outcomes have not been reached by some therapeutic modalities and no single modality is or can be perfect. Statistically significant improvements in these intermediate end points have been shown in "some" but not all studies. Although healing of esophagitis can be accomplished with either medical or surgical therapy, there is inadequate data with endotherapies, because most patients treated with endotherapies have had prior trials of proton pump inhibitors (PPIs) and hence healed their esophagitis. Effective prevention of complications, such as esophageal adenocarcinoma, remains challenging for all modalities. Patients who have not normalized their GERD-related quality of life with once or twice daily PPI therapy should undergo functional esophageal evaluation with pH testing and esophageal motility study and they should be evaluated by both an endoscopist and a surgeon. The decision on how to proceed should be made on the basis of the criteria for endotherapy and surgery, availability of local endoscopic and surgical expertise and patients' preference. Such multimodality therapy model is in many ways similar to the long-term management of coronary artery disease where pharmacotherapy, angioplasty, and bypass surgery are frequently used in tandem or in combination. Multimodality therapy aiming at normalization of GERD-related quality of life is an option today, and should be available to all patients in need of therapy. The target population for GERD endotherapy currently consists of PPI-dependent GERD patients, who have a small (<2-cm-long) or no sliding hiatal hernia, and without severe esophagitis or Barrett esophagus. Thus far, only Stretta and the NDO plicator have been studied in sham-controlled trials. Registries of complications suggest that these techniques are relatively safe, but serious morbidity, including rare mortality have been reported (for a continuous update on complications related to endoscopic therapies see: http://www.fda.gov/cdrh/maude.html). All can be performed on an outpatient basis, under intravenous sedation and local pharyngeal anesthesia. Future comparative studies with predetermined clinically significant end points, validated outcome measures, prolonged follow-up, and complete complication registries will eventually determine the precise role of endoscopic procedures for the patients with GERD.

Abstract

Esophageal reflux and Barrett's esophagus represent two major risk factors for the development of esophageal adenocarcinoma. Previous studies have shown that brief exposure of the Barrett's-associated adenocarcinoma cell line, SEG-1, or primary cultures of Barrett's esophageal tissues to acid or bile results in changes consistent with cell proliferation. In this study, we determined whether similar exposure to acid or bile salts results in gene expression changes that provide insights into malignant transformation.Using previously published methods, Barrett's-associated esophageal adenocarcinoma cell lines and primary cultures of Barrett's esophageal tissue were exposed to short pulses of acid or bile salts followed by incubation in culture media at pH 7.4. A genome-wide assessment of gene expression was then determined for the samples using cDNA microarrays. Subsequent analysis evaluated for statistical differences in gene expression with and without treatment.The SEG-1 cell line showed changes in gene expression that was dependent on the length of exposure to pH 3.5. Further analysis using the Gene Ontology, however, showed that representation by genes associated with cell proliferation is not enhanced by acid exposure. The changes in gene expression also did not involve genes known to be differentially expressed in esophageal adenocarcinoma. Similar experiments using short-term primary cultures of Barrett's esophagus also did not result in detectable changes in gene expression with either acid or bile salt exposure.Short-term exposure of esophageal adenocarcinoma SEG-1 cells or primary cultures of Barrett's esophagus does not result in gene expression changes that are consistent with enhanced cell proliferation. Thus other model systems are needed that may reflect the impact of acid and bile salt exposure on the esophagus in vivo.

Abstract

Colonoscopy is the "gold standard" for colorectal polyp and cancer detection, but important lesions may be missed on the proximal aspect of haustral folds, rectal valves, or flexures.Our purpose was to evaluate a prototype auxiliary imaging device that extends beyond the colonoscope's tip, providing a continuous retrograde view to detect lesions missed by the forward-viewing colonoscope.Three anatomic models of the colon were prepared with simulated polyps, 32% in obvious locations and 68% on the proximal aspect of folds. Six endoscopists examined each model with two methods. Method A used a standard video colonoscope. Method B involved an identical colonoscope with a retrograde-viewing auxiliary device positioned within its instrument channel. Order of testing was randomized and blinded.Laboratory bench.Detection rates for simulated polyps.Of 78 "obvious" polyps, 69 (88%) and 70 (90%) were detected by methods A and B, respectively (P > .9). In contrast, of 162 polyps on proximal aspects of folds, 20 (12%) and 131 (81%) were detected by methods A and B, respectively (P < .00001).Limitations resulted from (1) use of commercially available anatomic models in which haustral folds are less prominent and more rigid than in humans and (2) evaluation of a prototype device that had larger size and narrower angle of view than the planned production model and that was fixed in relation to the colonoscope.In simulated testing, a retrograde-viewing auxiliary imaging device used with a standard video colonoscope significantly improves detection rates of simulated polyps and promises to enhance the diagnostic yield of colonoscopy in humans.

Abstract

Advances in interventional endoscopic technology and techniques are paving the way for the increased application of minimally invasive methods to treat various upper gastrointestinal conditions, both benign and malignant. Through the description of enteral stenting for palliation of malignant obstruction, expanded techniques of enteral feeding tube placement, mucosectomy of early gastric cancer, and snare ampullectomy for benign ampullary lesions, this review focuses on recent progress in therapeutic endoscopy of the stomach and duodenum and highlights the importance of continued research and development.

Abstract

A potential reduction in symptoms related to atrial fibrillation after treatment of gastroesophageal reflux disease symptoms with proton pump inhibitor therapy has been previously described. However, illustration of this relationship by combined 24-hour pH and ambulatory Holter monitoring has not been performed. We report 3 patients with symptoms of both palpitations and reflux who underwent simultaneous Holter and 24-hour ambulatory pH monitoring off of antireflux therapy. All of the patients reported a reduction in arrhythmia symptoms on proton pump inhibitor therapy. The findings from this preliminary series suggest a potential relationship between gastroesophageal reflux disease and atrial arrhythmias that might improve with antireflux therapy. Patients with documentation of both atrial arrhythmias and reflux should have a trial of aggressive acid suppressive therapy To further confirm this relationship, larger prospective studies are needed to assess whether maximal acid suppression improves arrhythmias.

Abstract

Barrett's esophagus is a precursor of esophageal adenocarcinoma. DNA microarrays that enable a genome-wide assessment of gene expression enhance the identification of specific genes as well as gene expression patterns that are expressed by Barrett's esophagus and adenocarcinoma compared with normal tissues. Barrett's esophagus length has also been identified as a risk factor for progression to adenocarcinoma, but whether there are intrinsic biological differences between short-segment and long-segment Barrett's esophagus can be explored with microarrays.Gene expression profiles for endoscopically obtained biopsy specimens of Barrett's esophagus or esophageal adenocarcinoma and associated normal esophagus and duodenum were identified for 17 patients using DNA microarrays. Unsupervised and supervised approaches for data analysis defined similarities and differences between the tissues as well as correlations with clinical phenotypes.Each tissue displays a unique expression profile that distinguishes it from others. Barrett's esophagus and esophageal adenocarcinoma express a unique set of stromal genes that is distinct from normal tissues but similar to other cancers. Adenocarcinoma also showed lower and higher expression for many genes compared with Barrett's esophagus. No difference in gene expression was found between short-segment and long-segment Barrett's esophagus.The genome-wide assessment provided by current DNA microarrays reveals many candidate genes and patterns not previously identified. Stromal gene expression in Barrett's esophagus and adenocarcinoma is similar, indicating that these changes precede malignant transformation.

Abstract

The clinical spectrum of chronic intestinal dysmotility (CID) is not well known. We determined the spectrum of motor abnormalities, underlying pathology, clinical course, and response to treatment of adults with CID at a tertiary referral center.This was a descriptive retrospective analysis of a CID cohort conducted at a tertiary referral gastrointestinal (GI) motility center. A total of 113 referred patients underwent gastroduodenal manometry, other motility studies as appropriate, and radiologic and/or endoscopic assessment to exclude mechanical intestinal obstruction.Common symptoms included abdominal distention, abdominal pain, nausea, and constipation. The course was chronic with intermittent symptoms. Gastroduodenal manometry was abnormal in all patients; a pattern suggestive of a neuropathic process was the most common. Other GI motility studies showed delayed gastric, gallbladder, and colonic transit, nonspecific esophageal dysmotility, sphincter of Oddi hypertonicity, and poor rectal balloon sensation/expulsion. Treatment involved nutritional support, prokinetics, analgesics, antinausea agents, and laxatives, with variable response and high morbidity, multiple emergency admissions, need for nutritional support, and poor response to surgery. Nearly 40% of the patients underwent abdominal surgery.Patients with CID have a chronic course and high morbidity. Because any segment of the GI tract may be involved in CID, functional assessment of the entire GI tract is recommended. CID presents several unmet clinical needs even in tertiary centers with expertise.

Abstract

It has been suggested that Barrett's esophagus (BE) is associated with an increased risk of developing colorectal neoplasia, but this has not been reported consistently.To study whether BE is associated with an increased risk of colorectal neoplasia, and if it is, whether it is dependent on use of proton-pump inhibitors (PPIs) or aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs).Case-control study.Endoscopic database of the Palo Alto Veterans Affairs Health Care System.268 veterans with BE were matched with 268 controls without BE.Controls had undergone upper GI endoscopy within 14 days of the corresponding case. Colonoscopy was performed within 6 months in cases and controls.Development of colorectal neoplasia.Colorectal neoplasia was present in 162 of 268 (60%) BE patients and in 105 of 268 (40%) controls (p < 0.001). The presence of BE (odds ratio [OR] 2.02: 95% CI [1.35, 3.04]), but also increasing age (OR 1.24 per decade: 95% CI [1.04, 1.48]) and alcohol use (OR 1.70: 95% CI [1.16, 2.50]) were associated with an increased risk of colorectal neoplasia in multivariable logistic regression analysis, whereas PPIs (OR 0.99: 95% CI [0.66, 1.48]) and aspirin/NSAIDs (OR 0.90: 95% CI [0.61, 1.33]) had no meaningful effect.This was a retrospective study in mostly male veterans.Veterans with BE are at an increased risk of developing colorectal neoplasia. This association is independent from the use of PPIs or aspirin/NSAIDs.

Abstract

To evaluate the efficacy and upper gastrointestinal (UGI) safety of celecoxib, compared with nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs), among patients with osteoarthritis.A total of 13274 osteoarthritis patients from 39 countries were randomly assigned to double-blind treatment with either celecoxib 100 mg twice daily (BID), celecoxib 200 mg BID, or nonselective NSAID therapy (diclofenac 50 mg BID or naproxen 500 mg BID) for 12 weeks. Standard validated measures were used to assess osteoarthritis efficacy. Serious UGI events were evaluated by 2 blinded, independent, gastrointestinal events committees.Results from all primary efficacy assessments showed that both dosages of celecoxib were as effective as NSAIDs in treating osteoarthritis. Significantly more ulcer complications occurred within the nonselective NSAID group (0.8/100 patient-years) compared with the celecoxib group (0.1/100 patient-years) (odds ratio = 7.02; 95% confidence interval [CI], 1.46 to 33.80; P =.008). There were fewer ulcer complications in the celecoxib group compared with the NSAID group, both in patients taking concomitant aspirin and those not taking aspirin, but the difference reached statistical significance only in the latter comparison. The number of cardiovascular thromboembolic events was low and not statistically different between the groups (eg, myocardial infarction rates: celecoxib 10 events [0.55/100 patient-years] vs NSAIDs 1 event [0.11/100 patient-years], (P =.11), but the study was not powered to detect such differences.In the treatment of osteoarthritis, celecoxib is as effective as the nonspecific NSAIDs naproxen and diclofenac, but has significantly fewer serious upper gastrointestinal events.

The role of antisecretory therapy in the management of non-variceal upper gastrointestinal bleedingALIMENTARY PHARMACOLOGY & THERAPEUTICSTriadafilopoulos, G.2005; 22: 53-58

Abstract

Non-variceal, upper gastrointestinal bleeding accounts for 300,000 hospitalizations annually in the US and the risk of rebleeding and mortality remain high. The aim of this study was to review the incidence and causes of non-variceal upper gastrointestinal haemorrhage, criteria for early discharge, risk stratification and intravenous vs. oral proton-pump inhibitor use. Peptic ulcer disease accounts for 45% of all admissions for upper gastrointestinal bleeding. Clinical and endoscopic predictors of adverse outcome have been identified. The Rockall scoring system identifies patients who can be considered for early discharge after endoscopy. Evidence supports the use of intravenous proton-pump inhibitor therapy for patients with bleeding ulcers associated with high-risk stigmata. Patients who are clinically stable and in whom upper endoscopy has shown an ulcer with a clean base or a flat pigmented spot have a low risk for rebleeding and may be discharged early on oral proton-pump inhibitor therapy. Proton-pump inhibitor treatment reduces ulcer rebleeding but does not affect overall mortality. In the US, most patients with ulcer bleeding have low-risk stigmata, and thus, can be treated with oral proton-pump inhibitors and discharged early.

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastrointestinal adverse effects, ranging from dyspepsia and peptic ulcer disease to more serious complications such as haemorrhage or perforation. NSAID-induced gastrointestinal toxicity is a significant medical problem worldwide. Misoprostol is effective in reducing NSAID-induced mucosal damage, but patient compliance is limited by poor tolerance. Histamine receptor antagonists are relatively effective against duodenal ulcers but offer no significant protection against gastric ulcers. Proton pump inhibitors (PPIs), such as pantoprazole, omeprazole and lansoprazole, have been shown to be effective in preventing the development of gastric and duodenal ulcers in high-risk patients taking NSAIDs. PPI therapy is also beneficial in healing NSAID-induced ulcers and preventing their recurrence in patients requiring ongoing NSAID therapy. PPIs have an excellent safety profile, and pantoprazole--with its low potential for drug-drug interactions--is particularly suitable for administration to elderly patients who often require concomitant treatment with other medications.

Abstract

A significant percentage of patients with Barrett's oesophagus (BE) will continue to manifest abnormal intra-oesophageal pH profiles regardless of proton pump inhibitor (PPI) therapy.We conducted a prospective study in order to determine whether a change in PPI therapy would alter intra-oesophageal and intra-gastric acid suppression in BE patients.Seventeen Helicobacter pylori-negative BE patients (16 males, 1 female; mean+/-S.D. age, 63.5+/-13.2).Twenty-four-hour pH monitoring was performed on omeprazole or lansoprazole, followed by repeat pH monitoring on rabeprazole at a dose titrated for symptom relief. Patients completed validated symptom and health-related quality-of-life (HRQL) surveys while on and off therapy.Ten (59%) of the 17 patients had abnormal baseline intra-oesophageal pH profiles. Oesophageal pH monitoring values on rabeprazole were abnormal in five out of five (100%) of the omeprazole cohort and three out of five (60%) of the lansoprazole cohort that had abnormal pH profiles on initial testing. Intra-gastric pH control was inadequate in BE patients on all PPIs; the mean percentage time with intra-gastric pH below 4.0 was 46% on omeprazole, 71% on lansoprazole and 51% on rabeprazole (p=0.25). All of the patients demonstrated the phenomenon of nocturnal acid breakthrough while undergoing PPI therapy.Change in PPI therapy did not alter intra-oesophageal or intra-gastric control in patients with BE.

Abstract

The Stretta procedure is safe and effective for the treatment of GERD. There are well-documented clinical trial data supporting its use, including a randomized sham-controlled study, single- and multi-center prospective trials, and community practice reports. The complication rate is within the acceptable range for therapeutic endoscopic procedures and less than the published complication rate for laparoscopic fundoplication. The durability of effect also is established beyond 2 years in several studies. Stretta should be added to the GERD management algorithm specifically for patients considering an antireflux surgical procedure but who are not accepting of the risks of surgery and anesthesia. These patients typically present with incomplete GERD control, despite optimal antisecretory drug therapy, or intolerance to medical therapy. Stretta should be considered only for patients who fit the anatomic inclusion criteria, whereas antireflux surgery should be reserved for those who do not. The decision to undergo antireflux surgery or Stretta must be based on the relative risks and benefits of each procedure. Although antireflux surgery provides better control of esophageal acid exposure than Stretta, the outcomes for GERD symptoms, quality of life, and reduction in PPI use are comparable. Stretta has a low risk of acute adverse events, has no reported cases of long-term dysphagia, and obviates general anesthesia and hospitalization, whereas antireflux surgery has a reported adverse event rate of approximately 2%, a considerable incidence of dysphagia, and requires general anesthesia and 1 to 2 days in the hospital. Another advantage of the Stretta procedure is that antireflux surgery still can be performed in the case of failures. In conclusion, the Stretta procedure offers a minimally invasive, safe, and effective alternative to antireflux surgery for those patients who have GERD who are controlled unsatisfactorily on antisecretory medications, who are considering surgery, and who meet the anatomic criteria that make the procedure technically feasible and safe.

Abstract

With the increase in the rate of esophageal adenocarcinoma in the United States and the Western world matched with the high morbidity and mortality of esophagectomy, there is an increasing need for new and effective techniques to treat and prevent esophageal adenocarcinoma. A wide variety of endoscopic mucosal ablative techniques have been developed for early esophageal neoplasia. However, long-term control of neoplasic risk has not been demonstrated. Most studies show that specialized intestinal metaplasia may persist underneath neo-squamous mucosa, posing a risk for subsequent neoplastic progression. In this article we review current published literature on endoscopic therapies for the management of Barrett's esophagus.

Abstract

Gastroesophageal reflux disease is a chronic disease that adversely affects health-related quality of life. The purpose of this study was to derive health state utilities for patients with chronic heartburn symptoms.We used a custom-designed computer program in order to elicit utilities with the time-tradeoff and standard-gamble techniques. Patients with chronic (more than 6 months) symptoms of gastroesophageal reflux disease entered the study. Two interviews were performed in random sequence either initially on medications for heartburn that adequately controlled symptoms, or off of medications for 1 wk while the patient was symptomatic. We also collected data using visual-analog scales, quality of life in reflux and dyspepsia (QOLRAD), and Gastrointestinal Symptom Rating Scale (GSRS) scores.We invited 222 patients to participate; 158 (71%) patients (129 men, 29 women) completed the study. Barrett's esophagus was present in 40 (25%), erosive disease in 17 (11%), and 118 (74%) had comorbid conditions. The mean (+/-SD) utility ratings were 0.94 +/- 0.09 on medical therapy and 0.90 +/- 0.12 off medications for patients with reflux alone using time tradeoff (p= 0.004), and 0.94 +/- 8.0 both on and off of antireflux medications with standard-gamble assessment (p= 0.96). Mean time-tradeoff scores were also significantly lower off of medications for patients with other comorbid conditions (p= 0.002). There was no significant difference between mean utility scores for patients with or without Barrett's esophagus or erosive disease.Gastroesophageal reflux disease adversely affects health-related quality of life. Time-tradeoff utility for patients with reflux disease is substantially higher when patients are on medication than off medications.

Abstract

The diagnostic utility of 24-h oesophageal ambulatory pH monitoring in patients with functional dyspepsia has not been well established.We performed a prospective study of oesophageal pH monitoring in patients with functional dyspepsia in order to assess whether a positive pH test might predict response to proton pump inhibitor therapy in a subset of functional dyspepsia patients.Forty Helicobacter pylori-negative functional dyspepsia patients (35 males and 5 females, mean age (+/-S.E.M.) of 54+/-2.4 years) with predominantly unspecified dyspepsia subtype and normal distal oesophageal biopsies.All subjects were randomised in a double-blind fashion to either omeprazole 20 mg/day or placebo daily for four weeks after 24-h pH monitoring.Twenty-four-hour pH monitoring was abnormal in 9 of the 21 patients (43%) in the omeprazole group and 5/19 (26%) of the placebo group (p=NS). Patients who reported symptomatic improvement on the Gastrointestinal Symptom Rating Scale were no more likely to have abnormal scores on pH monitoring than patients who did not have symptomatic response.Although approximately one-third of functional dyspepsia patients will have abnormal profiles on 24-h ambulatory oesophageal pH monitoring, an abnormal score does not appear to predict response to proton pump inhibitor therapy in patients with unspecified functional dyspepsia.

Abstract

Photodynamic therapy appears to be effective in ablating high-grade dysplasia in Barrett's esophagus. Our aim was to identify the most effective and cost-effective strategy for managing high-grade dysplasia in Barrett's esophagus without associated endoscopically visible abnormalities.By using decision analysis, the lifetime costs and benefits of 4 strategies for which long-term data exist were estimated by us: esophagectomy, endoscopic surveillance, photodynamic therapy, followed by esophagectomy for residual high-grade dysplasia; and photodynamic therapy followed by endoscopic surveillance for residual high-grade dysplasia. It was assumed by us that there was a 30% prevalence of cancer in high-grade dysplasia patients and a 77% efficacy of photodynamic therapy for high-grade dysplasia and early cancer.Esophagectomy cost 24,045 dollars, with life expectancy of 11.82 quality-adjusted life years. In comparison, photodynamic therapy followed by surveillance for residual high-grade dysplasia was the most effective strategy, with a quality-adjusted life expectancy of 12.31 quality-adjusted life years, but it also incurred the greatest lifetime cost (47,310 dollars) for an incremental cost-effectiveness of 47,410 dollars/quality-adjusted life years. The results were sensitive to post-surgical quality of life and survival, and to cancer prevalence if photodynamic therapy efficacy for cancer was less than 50%.Photodynamic therapy followed by endoscopic surveillance for residual high-grade dysplasia appears to be cost effective compared with esophagectomy for patients diagnosed with high-grade dysplasia in Barrett's esophagus. Clinical trials directly comparing these strategies are warranted.

Abstract

Endoscopic screening and periodic surveillance for patients with Barrett's esophagus has been shown to be cost-effective in patients with esophageal dysplasia, with treatment for esophageal cancer limited to esophagectomy. Most gastroenterologists refer patients with high-grade dysplasia for esophagectomy, and effective endoscopic therapies are available for nonoperative patients with esophageal cancer. The cost-effectiveness of screening strategies that incorporate these nonsurgical treatment modalities has not been determined.We designed a Markov model to compare lifetime costs and life expectancy for a cohort of 50-year-old men with chronic reflux symptoms. We compared 10 clinical strategies incorporating combinations of screening and surveillance protocols (no screening, screening with periodic surveillance for both dysplastic and nondysplastic Barrett's esophagus, or periodic surveillance for dysplasia only), treatment for high-grade dysplasia (esophagectomy or intensive surveillance), and treatment for cancer (esophagectomy or surgical and endoscopic treatment options).Screening and surveillance of patients with both dysplastic and nondysplastic Barrett's esophagus followed by esophagectomy for surgical candidates with high-grade dysplasia or esophageal cancer and endoscopic therapy for cancer patients who were not operative candidates cost $12,140 per life-year gained compared to no screening. Other screening strategies, including strategies that had no endoscopic treatment options, were either less effective at the same cost, or equally effective at a higher cost.The cost-effectiveness of screening and subsequent surveillance of patients with dysplastic as well as nondysplastic Barrett's esophagus followed by endoscopic or surgical therapy in patients who develop cancer compares favorably to many widely accepted screening strategies for cancer.

Abstract

Gastroesophageal reflux disease (GERD) is as common in women as in men, and may present with various symptoms, such as heartburn, regurgitation, dysphagia, or chest pain. In this study, we evaluated the patterns of symptomatic GERD and the spectrum of disease activity in women and compared them to a cohort of disease- and age-matched men.We studied 543 adults, both men and women, referred for evaluation because of symptoms or signs suggestive of GERD. All patients were assessed immediately before testing using a standardized symptom questionnaire. Endoscopic, ambulatory pH, and motility findings were categorized and graded according to their extent and severity. The prevalence, nature, and severity of esophageal symptoms and their relationship to endoscopic disease severity were then analyzed. Comparisons were made between the two groups, i.e., 341 men (mean age 54, age range 25-90) and 202 women (mean age 50, age range 22-80).Heartburn without esophagitis was noted in 38% of men and 55% of women patients. Hiatal hernia was noted in 28% of men and in 26% of women. There were no differences in the magnitude of esophageal acid exposure by pH criteria and motility abnormalities between the two groups. The prevalence of endoscopic stages of GERD (0-IV, Savary-Miller classification) was similar between the two groups (p > 0.1, chi2 test) but women were less likely to harbor Barrett's esophagus (p < 0.05, chi2 test). Quantitative esophageal symptom analysis revealed significantly higher symptom severity scores for heartburn (p < 0.01), regurgitation (p < 0.05), belching (p < 0.01), and nocturnal (p < 0.01) symptoms in women as compared to men. Women also experienced higher symptoms scores of lower abdominal symptoms, such as abdominal pain, diarrhea, and constipation (p < 0.01).Among symptomatic adults undergoing evaluation for GERD, women appear to have generally similar patterns of endoscopic severity of GERD as men but they are less likely to harbor Barrett's esophagus. The severity of symptoms in women is significantly more than in men and may contribute to earlier disease recognition and different disease management.

Abstract

To assess the risk of serious gastrointestinal and thromboembolic complications with approved doses of meloxicam.We pooled data from clinical trials of meloxicam at doses of 7.5 or 15 mg/d. A blinded gastrointestinal adjudication committee used prespecified criteria to identify gastric or duodenal perforation, gastric outlet obstruction, or hemodynamically important upper gastrointestinal bleeding. For analysis of thromboembolic complications, investigator-reported events were analyzed without adjudication.We analyzed data from 24,196 patients from 28 trials, most of whom had been followed for up to 60 days. Of these patients, 13,118 received meloxicam (10,158 received a daily dose of 7.5 mg and 2960 received 15 mg), 5283 were treated with diclofenac 100 mg, 181 received diclofenac 150 mg, 5371 were treated with piroxicam 20 mg, and 243 received naproxen 500 mg twice daily. Patients who received 7.5 mg of meloxicam daily had a 0.03% risk of serious upper gastrointestinal events, which was significantly lower than the risk in those who received diclofenac, naproxen, or piroxicam (P <0.02). With the 15 mg daily dose of meloxicam, this risk was significantly different only when compared with piroxicam (P = 0.03). The risk of thromboembolic events in patients treated with meloxicam at either dose was lower than with diclofenac, but similar to that observed with piroxicam and naproxen.This pooled analysis of 24,196 patients demonstrates that meloxicam has a favorable gastrointestinal and thromboembolic safety profile. However, only a small number of patients were followed for more than 60 days, and meaningful comparisons were not possible in this subgroup.

Abstract

Ulcerative colitis and Crohn's disease, the two main forms of inflammatory bowel disease (IBD), are chronic illnesses that affect hundreds of thousands of Americans. Patients with IBD suffer chronically from diarrhea, abdominal pain, gastrointestinal bleeding, malabsorption, and weight loss requiring continuous medical and surgical attention. Despite recent advances in therapy, IBD follows a course of exacerbations and remissions with approximately 25-50% of patients relapsing annually. Hence, these diseases are readily encountered in primary care and gastroenterology clinics. Though medical and surgical treatment options have improved significantly, little has been written about the psychosocial aspects of IBD. Currently, there is a paucity of data concerning effective communication methods enabling physicians to develop stronger rapport with patients suffering from IBD, the care of whom requires a multidisciplinary approach involving primary care physicians, gastroenterologists, and colorectal surgeons. Because IBD has a high morbidity, it is worthwhile to further investigate those social factors that will improve patients' quality of life. In this paper, we summarize some of the common problems that emerge when taking care of patients with IBD and provide initial guidelines based on the world literature regarding the management and education of patients with IBD. Both primary care physicians and specialists (gastroenterologists, colorectal surgeons) need to be aware of the questions and concerns of IBD patients and to be capable of dispensing the information in a clear and concise manner. Using the case scenario format, we review the most common aspects of communication for health care professionals taking care of IBD patients and suggest ways to establish and maintain long-term doctor-patient relationships. The two most significant interventions that dramatically improve quality of life and patient-physician relationships are proper patient education and appropriate treatment of concurrent depression and anxiety. We hope that our review will form a framework by which different members of the medical team learn their roles in the complex management decisions affecting IBD patients.

Abstract

Endoscopic radiofrequency energy delivery (Stretta) is effective for managing gastroesophageal reflux disease (GERD) in selected patients. One criticism, however, is a theory that a mechanism of action is partial desensitization of the esophageal body rather than a reduction in esophageal acid exposure. To resolve this question, this study sought to determine if there is a correlation between the improvement in GERD outcomes and esophageal acid exposure after Stretta.Subgroup analyses were performed between "responder" and "nonresponder" groups from the U.S. Stretta open label trial ( n = 118), on the basis of posttreatment responses for GERD health-related quality of life (HRQL) heartburn, satisfaction, and proton pump inhibitor use. Outcomes were analyzed within and between subgroups. Pearson correlation coefficient analysis was performed comparing distal esophageal acid exposure with each of the continuous outcomes (GERD-HRQL, heartburn, satisfaction).Responder subgroups had significant improvements in esophageal acid exposure, whereas nonresponders had no change or less improvement in the same. Changes in GERD-HRQL and heartburn severity were correlated with changes in acid exposure ( r = 0.16, p = 0.12 and r = 0.26, p = 0.01, respectively). Changes in satisfaction were negatively correlated with changes in esophageal acid exposure ( r = 0.23, p = 0.02) because satisfaction, as expected, increased as acid exposure decreased.Responders had significant improvement in esophageal acid exposure, whereas nonresponders had less or no change. There was a positive correlation between esophageal acid exposure and both GERD-HRQL and heartburn. This evidence suggests that symptomatic improvement after Stretta is attributable to a decrease in esophageal acid exposure and not to desensitization of the esophagus.

Abstract

Gastroesophageal reflux disease (GERD) is a very common disorder that affects substantially the patient's quality of life. A number of important new developments in the diagnosis, clinical management, and medical, endoscopic, and surgical therapies were described in 2003, and they are summarized here.Most patients with symptomatic GERD do not have erosive reflux disease. Transient lower esophageal sphincter relaxations and hiatal hernias have emerged as major and interacting factors in GERD. Stretch receptors in the fundus are more relevant than tension receptors in triggering transient lower esophageal sphincter relaxations and subsequent reflux. The wireless Medtronic Bravo pH system has been validated as an alternative to conventional pH monitoring and has better tolerability. The mainstay of medical therapy for GERD is the use of proton pump inhibitors, with as yet no superiority of any one agent over all others. Several endoscopic antireflux therapies aiming at creating an antireflux barrier and reducing or eliminating the need for chronic medical therapy or fundoplication have been introduced and validated as feasible, safe, and effective. It may be possible now to stratify patients with GERD to treatment with either endoscopic therapy or surgery according to the size of hiatal hernia, lower esophageal sphincter pressure, Barrett esophagus, and significant pulmonary symptoms.Key developments in the recognition and management of GERD in 2003 will have significant implications for clinical practice or research.

Abstract

Helicobacter pylori is the primary cause of peptic ulcer disease and an etiologic agent in the development of gastric cancer. H. pylori infection is curable with regimens of multiple antimicrobial agents, and antimicrobial resistance is a leading cause of treatment failure. The Helicobacter pylori Antimicrobial Resistance Monitoring Program (HARP) is a prospective, multicenter U.S. network that tracks national incidence rates of H. pylori antimicrobial resistance. Of 347 clinical H. pylori isolates collected from December 1998 through 2002, 101 (29.1%) were resistant to one antimicrobial agent, and 17 (5%) were resistant to two or more antimicrobial agents. Eighty-seven (25.1%) isolates were resistant to metronidazole, 45 (12.9%) to clarithromycin, and 3 (0.9%) to amoxicillin. On multivariate analysis, black race was the only significant risk factor (p < 0.01, hazard ratio 2.04) for infection with a resistant H. pylori strain. Formulating pretreatment screening strategies or providing alternative therapeutic regimens for high-risk populations may be important for future clinical practice.

Abstract

Acid plays a significant role in the development of gastroesophageal reflux symptoms, such as heartburn and regurgitation. It is generally assumed that acid suppressive therapy improves or eliminates symptoms by normalizing intraesophageal pH.The aim of this article was to assess the efficacy of proton-pump inhibitors (PPIs) in normalizing intraesophageal and intragastric pH in patients with GERD without Barrett's esophagus (BE) rendered symptom free by therapy.Patients were evaluated by dual-sensor 24-h pH monitoring while receiving PPI therapy for complete control of GERD symptoms. Analyses of intraesophageal and intragastric pH profiles were then made.Fifty patients, 39 men and 11 women, with GERD, without BE, were studied. All tolerated PPIs well and were asymptomatic at the time of the study. Fifty percent of patients had abnormal intraesophageal pH profiles despite adequate symptom control on PPIs, which was associated with significant breakthrough of intraesophageal acid control in both the upright and supine positions. Low intragastric pH correlated highly with intraesophageal acid reflux only in patients with persistent abnormal esophageal acid exposure (p= 0.001).Fifty percent of patients with GERD without BE continue to exhibit pathologic GERD and low intragastric pH despite PPI therapy that achieves complete reflux symptom control.

The management of anticoagulants in the periendoscopic period for patients with atrial fibrillation: A decision analysisAMERICAN JOURNAL OF MEDICINEGerson, L. B., Triadafilopoulos, G., Gage, B. F.2004; 116 (7): 451-459

Abstract

The management of patients who undergo endoscopy while being treated with warfarin is challenging. We used decision analysis to determine the preferred strategy to manage anticoagulants in the periendoscopic period.We designed a Markov model to estimate costs and quality-adjusted survival during a 10-year period in patients with nonvalvular atrial fibrillation undergoing screening colonoscopy. We compared six alternatives to the continue-warfarin strategy, which was to perform colonoscopy while the patient was taking full-dose warfarin. The hold-warfarin strategy was to stop warfarin 5 days before the colonoscopy. The repeat endoscopy strategy was to continue warfarin for a diagnostic colonoscopy, followed by a repeat procedure after cessation of warfarin if polypectomy was required. The dose-reduction strategy was to reduce the warfarin dose before colonoscopy. The low molecular weight heparin strategy was to administer subcutaneous low molecular weight heparin for 2 days before and 2 days after colonoscopy. The unfractionated heparin strategy was to administer intravenous unfractionated heparin for 2 days before and 2 days after the procedure. The vitamin K strategy was to hold warfarin for 4 days and to administer vitamin K if the international normalized ratio (INR) exceeded 2.0 the day before the procedure, or low molecular weight heparin if the INR was less than 1.5.For screening colonoscopy, assuming that polyps would be removed in 35% of examinations, the hold-warfarin and dose-reduction arms were both cost-effective strategies. The hold-warfarin arm was most cost-effective if the likelihood of polypectomy exceeded 60%, or if there was a low risk of stroke despite atrial fibrillation. The continue-warfarin strategy was preferred if the probability of polypectomy was 1% or less.Temporary warfarin cessation or halving the warfarin dose for several days before endoscopy was the preferred strategy for most patients. Periendoscopic heparin therapy was not cost-effective for patients with nonvalvular atrial fibrillation.

Abstract

Gastroesophageal reflux disease (GERD) is a common disorder that significantly affects patients' quality of life. Most patients with symptomatic GERD do not have erosive reflux disease. Frequent transient lower oesophageal sphincter relaxations and the presence of hiatal hernia have emerged as major and interacting factors in GERD. Several endoscopic anti-reflux therapies aiming at creating an anti-reflux barrier and reducing or eliminating the need for chronic medical therapy or fundoplication have been introduced and validated as feasible, safe and effective. Today, it is possible to manage GERD patients with a multioption approach of medical, endoscopic or surgical therapies according to the size of hiatal hernia, the lower esophageal pressure profile and their clinical response to single-modality therapy.

Abstract

Colonoscopic screening can detect neoplasms in asymptomatic adults, many of which would not be detected by sigmoidoscopy. However, because of cost and resource factors, many adults still undergo flexible sigmoidoscopy for colorectal cancer screening. In asymptomatic adults over age 50 undergoing unsedated flexible sigmoidoscopy screening, use of a colonoscope instead of a sigmoidoscope was studied to determine the feasibility, safety, tolerability, and yield.Over an 18-month period, asymptomatic adults referred for colorectal cancer screening by sigmoidoscopy were enrolled. Two experienced nurses attempted to reach the cecum by using a pediatric colonoscope but stopped if significant discomfort was experienced, if the preparation was suboptimal, or if polyps were found.A total of 672 adults (652 men, 20 women) underwent screening. The colonoscope was advanced beyond the level attainable with a sigmoidoscope (70-cm mark) in 240 cases. The cecum was reached in 110 (16.4%) of these patients, with a mean pain intensity for patients of 2.6 (scale 1-10) and a mean time for completion of the procedure of 17 minutes. Colonoscopy to the cecum was not feasible because of patient discomfort in 280 patients (41.7%), poor preparation in 179 (26.7%), left-sided polyps or cancer in 69, and/or severe diverticulosis and tortuosity in 34 cases. Twenty patients had polyps proximal to the 70-cm mark (65% adenomas, no cancer). There was no complication.The use of a colonoscope instead of a sigmoidoscope by nurses performing unsedated screening sigmoidoscopy is feasible, safe, and well-tolerated, and may improve the yield for screening by at least 16.4% in patients who would otherwise have had only the left colon examined.

Abstract

Eructation (belching) is a common symptom seen in clinical practice. Because either belching or heartburn may result from transient lower esophageal sphincter relaxations, it has been proposed that belching may be a manifestation of gastroesophageal reflux disease (GERD). In this retrospective study we evaluated the prevalence of belching in dyspepsia and GERD and the relation of belching to acid reflux events documented by pH monitoring.We examined the prevalence, frequency, and severity of belching and other GERD symptoms by use of standardized questionnaires in 180 GERD patients (group A) and 78 dyspeptic controls (group B) referred for evaluation at our institution. GERD was defined as either endoscopic esophagitis (or Barrett's esophagus) or positive DeMeester score (>14.2) on pH monitoring or both. Dyspeptic patients had normal endoscopy and pH studies. We also analyzed the relationship of belching to acid reflux events during the 24-h period of pH studies.Of 180 GERD patients, 132 (70%) reported belching during pH monitoring, versus 63 of 78 dyspeptic patients (80%) (p = ns). Similarly, 163 of 180 GERD patients (90%) reported heartburn versus 64 of 78 of dyspeptic patients (82%) (p = ns). Review of symptom questionnaires revealed no significant difference in belching severity between groups. However, heartburn and acid regurgitation were significantly more severe among GERD patients. There was a significantly higher correlation of both heartburn and belching with acid events in patients with GERD compared with patients with dyspepsia. In addition, although both belching and heartburn were significantly improved in patients with GERD, belching scores remained unchanged after proton pump inhibitor (PPI) therapy in patients with dyspepsia.Belching is as common and as severe in patients with dyspepsia as it is in patients with GERD. Belching and heartburn in GERD patients are more likely correlated with episodes of pathological acid reflux. Because belching cannot be clinically used as a discriminatory symptom, ambulatory pH monitoring should be considered to elucidate the relationship of belching to acid reflux in patients with dyspepsia or GERD.

Abstract

Exercise is beneficial to health because it reduces the risk of cardiovascular and endocrine diseases, improves bone and muscle conditioning, and lessens anxiety and depression. However, the impact of exercise on the gastrointestinal system has been conflicting. This systematic literature review evaluates the effect of the different modes and intensity levels of exercise on gastrointestinal function and disease using an evidence-based approach. Although more applicable to trained athletes and individuals who are highly active and, as such, at risk to experience the side-effects of exercise, an effort was made to state the level or degree of exercise or the lack of such evidence.Light and moderate exercise is well tolerated and can benefit patients with inflammatory bowel disease and liver disease. Physical activity can also improve gastric emptying and lower the relative risk of colon cancer in most populations. Severe, exhaustive exercise, however, inhibits gastric emptying, interferes with gastrointestinal absorption, and causes many gastrointestinal symptoms, most notably gastrointestinal bleeding.This knowledge will enable physicians to prescribe physical exercise in health and disease and to better manage patients with exercise-related gastrointestinal disorders. Our understanding of exercise and its gastrointestinal manifestations as well as risks and benefits warrants further investigation.

Abstract

The Stretta procedure is increasingly offered as first-line therapy before more invasive surgical procedures for selected patients with gastroesophageal reflux disease (GERD). Although a new addition to the clinical armamentarium, thus far the Stretta procedure appears to be a safe and effective technology for the treatment of GERD, with well-documented clinical trial data supporting its efficacy, safety, and patient satisfaction.

Abstract

The benchmarks in GERD therapy comprise the commonly prescribed anti-secretory drugs (H2RAs and PPIs) and anti-reflux surgery. Although drugs are typically safe, cost and patient compliance are challenges to long-term management. Furthermore, while heartburn may be controlled with aggressive medical therapy, other symptoms such as regurgitation may persist, reducing patient satisfaction and adversely affecting quality of life. Surgical anti-reflux procedures, most commonly laparoscopic Nissen fundoplication, improve GERD symptoms and normalize esophageal acid exposure in most patients. Patient perception of the potential risk of abdominal surgery and general anesthesia may limit willingness to undergo surgery resulting in only a small portion of GERD sufferers that actually undergo anti-reflux surgery each year. Overall, the Stretta procedure is well tolerated, with an acceptably low incidence of complications and obviates the need for anti-secretory drug therapy for most patients at the 6- and 12-month follow-up. GERD symptom scores, heartburn, satisfaction, and SF-36 scores significantly improve over the baseline and this effect lasts at least 12 months. The symptomatic improvement after Stretta at 12 months in one trial (GERD score, 27 to 9) is similar to that reported by Velanovich after fundoplication (GERD score, 27 to 3). Furthermore, the significant reduction in median esophageal acid exposure time (distal 10.6% to 6.2%, proximal 1.9% to 0.9%), provides objective evidence of an anti-reflux effect. Although the reported studies have been non-randomized, the objective improvement observed in esophageal acid exposure and the persistence of GERD symptom score improvement with repeated measure analysis over a course of 12 months make a significant placebo effect unlikely. Stretta is a promising new technology for the treatment of GERD that should be considered for patients who wish to discontinue a lifelong anti-secretory medication regimen or who have incomplete GERD symptom control on drugs, but are not yet accepting anti-reflux surgery.

Abstract

Barrett's esophagus is a metaplastic condition associated with gastroesophageal reflux disease and an increased risk for adenocarcinoma. Acid plays a significant role in the development and progression of Barrett's esophagus and high dose proton pump inhibitor (PPI) therapy is often needed. The aim of this study is to assess the efficacy of esomeprazole, a new potent PPI, on symptom relief and intraesophageal and intragastric acid suppression in patients with Barrett's esophagus (BE). Patients were evaluated by standardized questionnaires and dual sensor 24-h pH monitoring while receiving esomeprazole at a dose (40-80 mg/day) needed for control of symptoms. Analyses of intraesophageal and intragastric pH profiles were then made. Thirteen patients, mostly men, were studied. All tolerated esomeprazole (40-80 mg/day) with good symptom control. Sixty-two percent of patients with BE had abnormal intraesophageal pH profiles despite adequate symptom control on esomeprazole which was associated with significant breakthrough of intraesophageal acid control, particularly at night. Low nocturnal intragastric pH correlated highly with nocturnal intraesophageal acid reflux (P = 0.004) and there was a relative failure of nocturnal intragastric acid control with esomeprazole. A high percentage of patients with BE continue to exhibit pathologic GERD and low intragastric pH despite esomeprazole for reflux symptom control. For an antisecretory treatment aimed at chemoprevention of esophageal adenocarcinoma to be effective, higher PPI dosing confirmed by pH monitoring may be necessary.

Management of Barrett's esophagus with and without dysplasiaSCANDINAVIAN JOURNAL OF GASTROENTEROLOGYTriadafilopoulos, G.2003; 38: 40-46

Abstract

Barrett's esophagus (BE), a premalignant lesion to esophageal adenocarcinoma is associated with long-standing, gastroesophageal reflux disease (GERD). BE is a multi-phase process: during the initiation phase, genetically predisposed individuals (mostly white men) suffering from clinical or occult reflux damage their distal esophagus and form a new cell phenotype (incomplete intestinal metaplasia). During the formation phase, this phenotype occupies an area of variable surface (short or long-segment BE). During the progression phase, the metaplastic epithelium either remains dormant or progresses to dysplasia and adenocarcinoma. We review the recent clinical and basic research literature that explores the interaction of the refluxate (acid, bile, etc.) with BE. Acid and bile reflux variably affect BE and may cause dysplasia or adenocarcinoma. Regardless of the underlying biology, a patient with BE may suffer from GERD symptoms or may remain asymptomatic. Acid may be synergistic to bile or it could be antagonistic and protective. Acid suppressive therapy, if profound and continuous enough to abolish symptoms and esophageal acid exposure, may decrease proliferation, increase differentiation and reduce BE surface. Overexpression of cyclooxygenase-2 (COX-2), not entirely independent of acid/bile reflux, may increase proliferation and increase the invasiveness and metastatic potential of Barrett's metaplasia and neoplasia. Clinically, both acid and bile reflux need to be inhibited, either with potent acid-suppressing drugs or anti-reflux surgery. Cyclooxygenase inhibition using aspirin, NSAIDs or the safer COX-2 inhibitors added to these anti-reflux therapies may enhance the therapeutic benefit. Many questions remain unanswered. We still do not know why only a fraction of patients with GERD develop BE, what factors of the refluxate (acid, bile, etc.) initiate metaplasia and/or promote carcinogenesis, which patients are at risk for malignancy, and what is the best chemopreventive strategy. Ablation therapies and endoscopic mucosal resection are still under study.

Abstract

Adenocarcinoma of the esophagus and the gastroesophageal junction is the twentieth most common malignancy in the United States. In developed countries, the incidence of esophageal adenocarcinoma is increasing 5% to 10% per year. Despite the use of endoscopy for earlier detection, mortality from esophageal adenocarcinoma has not declined. Using an evidence-based approach, we review screening methods for esophageal adenocarcinoma, including the use of a symptom questionnaire, identification of patients with a family history of Barrett's esophagus, peroral or transnasal endoscopy, barium swallow, fecal occult blood testing, and brush and balloon cytology. Screening has not been shown to reduce rate of progression of Barrett's esophagus to esophageal cancer. Many treatment options for dysplastic Barrett's esophagus or early carcinoma appear effective, but long-term follow-up data are not available. There is currently insufficient evidence supporting population-based screening for Barrett's esophagus. Several risk factors, including severe reflux symptoms, male sex, and obesity, may identify patients with gastroesophageal reflux disease who are at the greatest risk of the development of cancer.

Abstract

The incidence of esophageal adenocarcinoma in the western world has been linked to chronic heartburn, regurgitation, and the development of the premalignant epithelium of Barrett's esophagus (BE). However, up to 40% of esophageal adenocarcinomas occur in patients without prior reflux symptoms. We prospectively screened for the presence of BE in asymptomatic subjects older than 50 years of age undergoing screening sigmoidoscopy for colorectal cancer.Subjects undergoing sigmoidoscopy for colorectal cancer (CRC) screening were invited to undergo upper endoscopy. Exclusion criteria included symptoms of gastroesophageal reflux disease (GERD) more than once a month, use of medications for GERD, or previous endoscopy. BE was classified as long-segment BE (LSBE), short-segment BE (SSBE), and microscopic specialized intestinal metaplasia of the esophagogastric junction (SIM-EGJ).Of 408 potential study candidates, 110 subjects were screened; 9 were women. The mean (+/-SD) age was 61 +/- 9.3 (range, 50-80) years, most of them (73%) Caucasian. Intestinal metaplasia (IM) extending above the EGJ was detected in 27 (25%) subjects; 8 (7%) had LSBE, and 19 (17%) had SSBE. Patients with BE were no more likely to be obese, consumers of tobacco or alcohol, report a family history of GERD, show association with toxic exposure, or use antacids more than once a month, compared with those without BE.BE was detected in 25% of asymptomatic male veterans older than 50 years of age undergoing screening sigmoidoscopy for CRC.

Abstract

Barrett's esophagus (BE) results from acid and bile reflux and predisposes to cancer. To further understand the mechanisms of acid- and bile-induced hyperproliferation in BE, we investigated the release of PGE(2) in response to acid or bile salt exposure. Biopsies of esophagus, BE, and duodenum were exposed to a bile salt mixture as a 1-h pulse and compared with exposure to pH 7.4 for up to 24 h, and PGE(2) release, cyclooxygenase-2 (COX-2), and protein kinase C (PKC) expression were compared. Similar experiments were also performed with acidified media (pH 3.5) alone, in the presence or absence of bisindolylmaleimide (BIM), a selective PKC inhibitor, and NS-398, a COX-2 inhibitor. One-hour pulses of bile salts or acid significantly enhanced proliferation, COX-2 expression, and PGE(2) release in BE. In contrast, the combination pulse of acid and bile salts had no such effect. Treatment with either BIM or NS-398 led to a dramatic decrease in PGE(2) release in BE explants and a suppression of proliferation. The acid- or bile salt-mediated hyperproliferation is related to PGE(2) release. Acid- and bile salt-induced induction of COX-2 and PKC may explain, at least in part, the tumor-promoting effects of acid and bile in BE.

Abstract

Although medical and surgical treatments are available for gastroesophageal reflux disease, endoscopic therapies for this condition are relatively new. This review describes the principles behind such treatments as well as the individual procedures themselves, focusing on mechanisms of action, safety and tolerability, and efficacy in animal and human clinical trials. Future trends in endoscopic therapy are discussed.

Abstract

Gastric acid is an important defence against enteric infection. Studies investigating the relationship between hypochlorhydria and enteric infections or gastric malignancy have been limited by difficulties in the non-invasive measurement of gastric acidity.To develop a blood test for hypochlorhydria based on the quininium resin test.Quininium resin dissociates to liberate free quinine at pH

Abstract

We evaluated the reasons for current practices in managing Barrett's esophagus. Using a questionnaire, we assessed the practices and beliefs of 162 Californian gastroenterologists in managing Barrett's esophagus, using descriptive statistics as well as multivariate logistic regression. Out of the 103 respondents, 87% screened for Barrett's esophagus in patients with > 12 months of reflux symptoms, but only 72% believed that screening would improve survival, and 48% believed it to be cost-effective. In total, 98% surveyed patients with long-segment Barrett's esophagus at least biennially (76% thought this would improve survival and 49% believed it to be cost-effective) and 82% surveyed short-segment Barrett's esophagus at least biennially (57% thought this would improve survival and 30% believed it to be cost-effective). Finally, 44% surveyed microscopic intestinal metaplasia at least biennially (26% thought this would improve survival and 11% believed it to be cost-effective). In total, 18% performed endoscopic ablation, whereas 3% referred patients with low-grade dysplasia and 85% referred patients with high-grade dysplasia for esophagectomy. Finally, 81% treated asymptomatic Barrett's esophagus patients with proton pump inhibitors, but only 56% believed that this would reduce the risk of cancer. Logistic regression showed that the only independent factor predictive of surveillance practices was belief in efficacy. Practice patterns tend to be more aggressive than those recommended by recent guidelines and those reported by previous surveys. Medico-legal considerations affect practice substantially.

Abstract

The delivery of temperature-controlled radiofrequency (RF) energy has been utilized effectively for the treatment of benign prostatic hyperplasia, sleep-disordered breathing, joint laxity, tumors, and cardiac dysrhythmias. The mechanism of action of RF delivery, depending on the specific disease pathophysiology, is related to wound contraction/remodeling or nerve pathway ablation. More recently, temperature-controlled RF energy delivery has been applied for the treatment of gastroesophageal reflux disease (GERD).To review the use of temperature-controlled RF energy in clinical applications, specifically the safety and efficacy data regarding endoluminal delivery of RF energy for the treatment of GERD (Stretta procedure).Endoluminal RF energy delivery to the gastroesophageal junction for the treatment of GERD is performed using conscious sedation on an outpatient basis. After treatment, medication use is significantly reduced or eliminated at 6 and 12 months, and there is a significant reduction in both the distal and proximal esophageal acid exposure on 24-hour ambulatory pH testing. All studies reviewed demonstrate improvement in GERD symptom scores, heartburn, satisfaction, and quality of life after treatment. There have been no cases of achalasia or stricture resulting from this procedure. Data support both an augmentation of the physical barrier function of the gastroesophageal junction and a reduction in triggering of transient LES relaxations as plausible mechanisms of action for this procedure.Endoluminal RF energy delivery has been shown in several studies to be safe and effective for the treatment of GERD and is a promising new technology for this chronic disorder.

Abstract

Postural measures are early recommendations in the management of heartburn, and are aimed at preventing acid reflux through an incompetent lower esophageal sphincter (LES). However, LES incompetence is found in only a minority of patients, and transient LES relaxations, primarily in the upright position, are currently recognized as the main pathophysiological abnormality in gastroesophageal reflux disease (GERD). We investigated the importance of supine acid reflux in patients with GERD.Upon review of their clinical, manometric, pH monitoring and endoscopic characteristics, 85 patients with reflux symptoms were classified into three groups: Group A (n=22), consisting of symptomatic patients without esophagitis or pathological reflux; group B (n=38), symptomatic patients with reflux but no endoscopic esophagitis; and group C (n=25), symptomatic patients with both ulcerative or complicated esophagitis and pathological reflux.All groups were similar in age distribution. Groups B and C had a higher prevalence of hiatal hernia and reflux symptoms. Manometry revealed similar LES pressures in groups A and B, but lower LES pressure in group C (P < 0.005). In groups A and B, supine reflux, in terms of percentage of time with pH < 4, was less pronounced than upright reflux (P < 0.0001). In contrast, group C supine reflux was as pronounced as the upright reflux.The majority of patients reflux in the upright position. Only patients with complicated esophagitis have significant bipositional acid reflux. These findings suggest that unless the patient has severe reflux disease, postural measures may not be indicated.

Abstract

Fecal occult-blood testing and sigmoidoscopy have been recommended for screening for colorectal cancer, but the sensitivity of such combined testing for detecting neoplasia is uncertain. At 13 Veterans Affairs medical centers, we performed colonoscopy to determine the prevalence of neoplasia and the sensitivity of one-time screening with a fecal occult-blood test plus sigmoidoscopy.Asymptomatic subjects (age range, 50 to 75 years) provided stool specimens on cards from three consecutive days for fecal occult-blood testing, which were rehydrated for interpretation. They then underwent colonoscopy. Sigmoidoscopy was defined in this study as examination of the rectum and sigmoid colon during colonoscopy, and sensitivity was estimated by determining how many patients with advanced neoplasia had an adenoma in the rectum or sigmoid colon. Advanced colonic neoplasia was defined as an adenoma 10 mm or more in diameter, a villous adenoma, an adenoma with high-grade dysplasia, or invasive cancer. Classification of subjects according to the findings was based on the most advanced lesion.A total of 2885 subjects returned the three specimen cards for fecal occult-blood testing and underwent a complete colonoscopic examination. A total of 23.9 percent of subjects with advanced neoplasia had a positive test for fecal occult blood. As compared with subjects who had a negative test for fecal occult blood, the relative risk of advanced neoplasia in subjects who had a positive test was 3.47 (95 percent confidence interval, 2.76 to 4.35). Sigmoidoscopy identified 70.3 percent of all subjects with advanced neoplasia. Combined one-time screening with a fecal occult-blood test and sigmoidoscopy identified 75.8 percent of subjects with advanced neoplasia.One-time screening with both a fecal occult-blood test with rehydration and sigmoidoscopy fails to detect advanced colonic neoplasia in 24 percent of subjects with the condition.

Abstract

Esophageal disease research is impeded by a paucity of nonmalignant cell lines. Furthermore, culture of primary esophageal cells is difficult because of a lack of cell adhesion and contamination. The aim of this study was to develop a short-term culture method to facilitate cell physiologic studies by using primary esophageal cells.By using a cytology brush, squamous and Barrett's epithelial cells were obtained from the esophagus of patients undergoing upper endoscopy. Cells were brushed onto chamber slides and allowed to adhere to the surface. Primary culture media was then added and cells were maintained at 37 degrees C for up to 72 hours. Cell yield and viability were calculated after trypan blue staining. For cell physiologic studies, cells were loaded with pH-sensitive dye BCECF-AM and intracellular pH measured on a dual excitation fluorescence microscope after an ammonium chloride prepulse. At the end of the physiologic experiments, cells were fixed in methanol and acetone and the cell type was verified with cytokeratin immunocytochemistry.Viable human esophageal cells were maintained in culture for up to 72 hours. The cells extruded trypan blue, and BCECF-AM was cleaved to BCECF by an intact cell membrane and permitted intracellular pH measurements. The epithelial cell origin of the cells was confirmed by cytokeratin staining. There was no contamination over the culture period and no overgrowth by lymphocytes or fibroblasts.This novel adaptation of brush cytology technique enables short-term culture of esophageal cells for in vitro studies. This rapid, simple primary culture technique is suitable for endoscopy and does not require the immediate, time-consuming laboratory techniques.

Abstract

Accurately predicting Barrett's esophagus (BE) in patients with gastroesophageal reflux disease (GERD) is difficult. Using logistic regression analysis of symptom questionnaire scores we created a model to predict the presence of BE.We conducted a logistic regression analysis of symptom data collected prospectively on 517 GERD patients and created a prediction model based on patient gender, age, ethnicity, and symptom severity.There were 337 (65%) males and 180 (35%) females, of whom 99 (19%) had Barrett's esophagus (BE). Multiple logistic regression analysis was performed to determine the predictive ability of gender, age, and ethnicity along with symptoms of heartburn, nocturnal pain, odynophagia, presence of belching, dysphagia, relief of symptoms with food, and nausea. The only significant predictors (at the 0.05 level) were male gender, heartburn, nocturnal pain, and odynophagia (all with positive effects on the presence of BE) and dysphagia (which had a negative effect). A nomogram was produced to show the effect of a given predictor on the probability of having BE in the context of the effects of the other predictors, and to estimate the probability of having BE for a given individual. The mean score (+/-SD) for the BE patients in our sample was 397.4+/-46.2 with a range of 292-530. For the patients without BE, the mean score (+/-SD) was 351.3+/-60.3 with a range of 190 - 528 (p < 0.001). If screening for BE is performed at a score of 375 or more, our model would have a specificity of 63% with a sensitivity of 77% (95% CI 61-86% given the 63% specificity).By asking seven questions about symptom severity, clinicians may be able to assign a probability to the presence of BE, and thus, determine the need for endoscopy in GERD patients.

Abstract

We explored the potential of early decompressive colonoscopy with intracolonic vancomycin administration as an adjunctive therapy for severe pseudomembranous Clostridium difficile colitis with ileus and toxic megacolon.We reviewed the symptoms, signs, laboratory tests, radiographic findings, and outcomes from the medical records of seven patients who experienced eight episodes of severe pseudomembranous colitis with ileus and toxic megacolon. All seven patients underwent decompressive colonoscopy with intracolonic perfusion of vancomycin.Fever, abdominal pain, diarrhea, abdominal distention, and tenderness were present in all patients. Five of seven patients were comatose, obtunded, or confused, and six of the seven required ventilatory support. The white blood cell count was greater than 16,000 in seven cases (six patients). Colonoscopy showed left-side pseudomembranous colitis in one patient, right-side colitis in one patient, and diffuse pseudomembranous pancolitis in five patients. Two patients were discharged with improvement. Five patients had numerous medical problems leading to their death. Complete resolution of pseudomembranous colitis occurred in four patients. One patient had a partial response, and two patients failed therapy.Colonoscopic decompression and intracolonic vancomycin administration in the management of severe, acute, pseudomembranous colitis associated with ileus and toxic megacolon is feasible, safe, and effective in approximately 57% to 71% of cases.

Abstract

The question of whether patients presenting for inguinal hernia repair require pre-operative assessment for colon cancer has remained unanswered. A case-control study is necessary to assess whether the prevalence of premalignant or malignant colonic lesions is higher in patients presenting with inguinal hernia compared to the general population.Between 1990-2000, 614 inguinal herniorrhaphies were performed at the Veterans Affairs Palo Alto Health Care System (VAPAHCS). We retrospectively studied the 149 (24%) patients from this group with no prior history of colonic polyps, malignancy, or gastrointestinal bleeding who had flexible sigmoidoscopy or colonoscopy performed during the peri-operative period. Comparison was made to 149 controls undergoing colonoscopy or sigmoidoscopy during the same time period for colon cancer (CRC) screening.The mean (+/-SEM) patient age was 67 +/- 0.7 (range 31-92) yr in the hernia patients and 66 +/- 0.8 (range 46-93) in the control group (p = 0.7). Eighty-two of the inguinal hernia patients had screening procedures performed preoperatively with a mean time (+/-SEM) of 1.4 +/- 0.14 yr, while endoscopy was performed in the post-operative period for the remaining 67 patients (average time 2.7 +/- 0.2 yr, p < 0.001). More patients underwent colonoscopy in the control group compared to the hernia cohort (p = 0.004). Seven (5%) patients in the hernia group were found to have colorectal cancer compared to six (4%) in the control group (p = 0.8).This study does not support previously published findings that patients with inguinal hernias are more likely to have premalignant colonic lesions. Patients with inguinal hernias should undergo screening for colon cancer at the same rate as the general population.

Abstract

The proton pump inhibitors (PPIs) are the most effective antisecretory agents used to treat acid-related disorders. As such, they are frequently prescribed for patients who are concurrently using other medications. PPIs may interact with other drugs through numerous mechanisms. The most important include competitive inhibition of hepatic cytochrome P (CYP) 450 enzymes involved in drug metabolism, and alteration of the absorption of other drugs via changes in gastric pH levels. Poor metabolizers, who lack CYP2C19, may be particularly predisposed to drug interactions. Although the potential for drug interactions is high, few clinically significant interactions have been reported for the PPIs. Nevertheless, caution is indicated when certain drugs are co-prescribed with these agents. The incidence of clinically significant drug interactions increases proportionately with the number of drugs taken and with the age of the patient. The drug interaction with the greatest clinical importance is the reduction in benzodiazepine clearance by omeprazole.

Abstract

Barrett's oesophagus, a significant complication of gastro-oesophageal reflux disease (GERD), is the single most important risk factor for oesophageal adenocarcinoma. The strong association between Barrett's oesophagus and chronic GERD suggests that abnormal oesophageal acid exposure plays an important role in this condition. The progression of Barrett's oesophagus from specialized intestinal metaplasia to dysplasia and finally invasive carcinoma is incompletely understood, but increased and disordered proliferation is a key cellular event. In ex vivo organ culture experiments, cell proliferation is increased after exposure to short pulses of acid, whilst proliferation is reduced in Barrett's oesophagus specimens taken from patients with oesophageal acid exposure normalized by antisecretory therapy. In long-term clinical studies, consistent and profound intra-oesophageal acid suppression with proton pump inhibitors decreases cell proliferation and increases differentiation in Barrett's oesophagus, but the clinical importance of such favourable effects on these surrogate markers is not clear. In clinical practice, proton pump inhibitors relieve symptoms and induce partial regression to squamous epithelium, but abnormal oesophageal acid exposure and the risk for dysplasia or adenocarcinoma persist in many patients. The ability of proton pump inhibitors to suppress acid profoundly and consistently may be critical in the long-term management of Barrett's oesophagus.

Abstract

Clostridium difficile is the etiological agent of antibiotic-associated diarrhea and pseudomembranous colitis and is a leading cause of nosocomial diarrhea. The objective of the study was to examine if leukocytosis could be a harbinger and surrogate marker of C. difficile infection in hospitalized patients.We retrospectively examined the medical records of 70 hospitalized patients who presented with diarrhea of variable severity and who underwent stool examination for enteric pathogens, including C. difficile. We specifically recorded the white blood cell count and the pattern and severity of leukocytosis in two groups of patients--those who were C. difficile-positive and those who were negative.Leukocytosis was common in C. difficile-positive patients, compared to in C. difficile-negative patients (mean 15,800/mm3 vs 7700/mm3, p < 0.01). Review of the 35 C. difficile-positive patients revealed three patterns: Pattern A) sudden WBC increase coinciding with the onset of symptoms suggestive of C. difficile; Pattern B) unexplained leukocytosis preceding the appearance of C. difficile-related diarrhea and serving as a harbinger of the infection; and Pattern C) worsening of pre-existing leukocytosis as a surrogate marker of C. difficile infection. Treatment with metronidazole led to amelioration of symptoms and normalization of the leukocyte count in all cases.Infection with C. difficile should be considered in the differential diagnosis of sudden onset of leukocytosis in hospitalized patients previously or concurrently treated with antibiotics. Doing so may obviate the need for expensive and time-consuming tests for other etiologies.

Abstract

In Asian populations, there is a high prevalence of right-sided colonic diverticulosis, the cause of which is uncertain. It is suspected that dietary habits may interact with a congenital predilection to cause this condition. To evaluate the relationship between long-term dietary habits and the prevalence of right-sided diverticulosis in the general population, we performed a retrospective case-control study.We reviewed the records of 3,105 screening colonoscopies performed on healthy, asymptomatic adults. All cases of right-sided diverticulosis were selected, and a similar number of gender-matched and age-matched controls with negative colonoscopies were randomly sampled from the same cohort. All case and control subjects were interviewed by a single-blinded nurse to establish their dietary habits during the past decade, in addition to other demographic characteristics. Based on consumption frequency, they were assigned to one of three diet classes for each of three food categories of interest: meat, vegetable, and fruit products. Staple foods such as rice were not included. Odds ratios were then calculated using multivariate conditional logistic regression and tests for trend were performed.A total of 86 cases of right-sided diverticulosis were included, whereas 106 controls were randomly selected. There was a marked association between meat consumption frequency and right-sided diverticulosis, with a trend P value of <0.01 and an odds ratio of 24.81 between the most and least frequent consumers of meat products.The prevalence of right-sided diverticulosis is strongly positively associated with past meat consumption frequency. There is no association with vegetable or fruit consumption frequency, laxative use, supplemental fiber intake, smoking, or family history.

Abstract

The management of the patient with inflammatory bowel disease (IBD) is challenging for both the physician and the patient. IBD imposes both a physical and emotional burden on patients' lives. Palliative care is important for IBD patients because it focuses on improving quality of life. While palliative care does not change the natural history of the disease, it provides relief from pain and other distressing symptoms. This article focuses on various aspects of care for IBD patients including pain control, management of oral and skin ulcerations, stomal problems in IBD patients, control of nausea and vomiting, management of chronic diarrhea and pruritus ani, evaluation of anemia, treatment of steroid-related bone disease, and treatment of psychological problems associated with IBD. Each of these areas is reviewed using an evidence-based approach. Evidence in category A refers to evidence from clinical trials that are randomized and well controlled. Category B Evidence refers to evidence from cohort or case-controlled studies. Category C is evidence from case reports or flawed clinical trials. Evidence from category D is limited to the clinical experience of the authors. Evidence labelled as category E refers to situations where there is insufficient evidence available to form an opinion. Algorithms for management of pain and nausea in IBD patients are presented.

Abstract

In December 1997, the American Society of Gastrointestinal Endoscopy (ASGE) issued guidelines regarding periendoscopic management of patients who take anticoagulants. They recommended that physicians substitute heparin for warfarin in their patients who have highly thrombotic conditions (e.g., a mechanical valve in the mitral position), and who will undergo high-risk procedures (e.g., polypectomy). The purpose of this study was to assess whether patient outcomes and anticoagulant management changed after the publication of the 1997 guidelines.We collected utilization data on all 104 patients at the Veterans Affairs Palo Alto Health Care System who were taking chronic warfarin therapy and who underwent endoscopic procedures during the study period (1996-1999). These patients underwent 99 colonoscopies, 63 upper endoscopies, and nine endoscopic retrograde cholangiopancreatographies. According to the ASGE guidelines, 18 of these patients had highly thrombotic conditions, whereas the remaining 86 patients had relatively low thrombotic conditions. We calculated their costs for intravenous or subcutaneous heparin therapy from the perspective of society. We followed-up all patients for 3 months, to determine the incidence of thrombotic and hemorrhagic outcomes.No patient suffered a thromboembolism or a hemorrhage; thus, the adverse-event rate (95% confidence interval) was 0% (0-3%). As recommended by the ASGE guidelines, all five (100%) patients who had highly thrombotic conditions had heparin substituted for warfarin before undergoing high-risk procedures. This strategy was also followed in 44 (27%) of the 166 procedures in other patients: 16 high-risk procedures in low-risk patients, and 28 low-risk procedures (in 20 low-thrombotic patients and in eight high-thrombotic patients). There was no significant difference between the management of any patients before and after the publication of the guidelines. The average cost per course of heparin therapy (typically 2 days intravenous heparin preprocedure, and 3 days heparin administered subcutaneously postendoscopy) was $1684. In all, 44 (90%) of 49 courses of heparin substituted for warfarin therapy were not recommended by the guidelines.Patients treated by the ASGE guidelines had the same 0% rate of thrombosis as patients who received periendoscopic heparin outside of the guidelines. Following the ASGE guidelines in all patients would have reduced the use of heparin therapy by 90%, for a net savings of $74,100.

Abstract

Barrett's esophagus (BE) results from acid and bile reflux and predisposes to cancer. We investigated the effect of bile salts, with or without acid, on cell proliferation in BE and assessed mechanism(s) involved. To mimic physiological conditions, biopsies of esophagus, BE, and duodenum were exposed to a bile salt mixture, either continuously or as a 1-h pulse, and were compared with control media without bile salts (pH 7.4) for < or =24 h. Similar experiments were also performed with acidified media (pH 3.5) combined with the bile salt mixture as a 1-h pulse. Cell proliferation was assessed by a [(3)H]thymidine incorporation assay with or without bisindolylmaleimide (BIM), a selective protein kinase C inhibitor. Bile salt pulses enhanced cell proliferation in BE without affecting cell proliferation in esophageal or duodenal epithelia. In the presence of BIM, there was complete obliteration of the bile salt-induced BE hyperproliferation. In contrast, 1-h pulses of bile salts in combination with acid significantly inhibited proliferation in BE but had no effect on esophagus or duodenum. We conclude that in BE explants, brief exposure to bile salts, in the absence of acid, increases proliferation, whereas exposure to a combination of bile salts and acid together inhibits proliferation.

Abstract

Omeprazole was replaced by lansoprazole as the only proton pump inhibitor on the Veterans Affairs (VA) formulary in February 1997. We aimed to assess the clinical and fiscal impact of this conversion at two VA hospitals.We identified lansoprazole intolerant patients using pharmacy databases. We reviewed medical records to obtain data regarding reasons for lansoprazole intolerance. The costs of the formulary change and the savings to the VA were calculated.A total of 3833 patients required long-term proton pump inhibitor therapy; 2224 (58%) were started on lansoprazole and 1479 (39%) were converted from omeprazole to lansoprazole. The remaining 130 (3.4%) patients were never converted from omeprazole to lansoprazole. Of the 3833 patients, 325 (8.5%) currently receive omeprazole therapy; of these, 195 out of 3703 (5.3%) patients are true lansoprazole failures; 172 of these 195 patients completed the study. Most (87%) of the lansoprazole intolerant patients received prior omeprazole. Discontinuation of lansoprazole was due to poor symptom control in 69% and/or side-effects (22%) including diarrhoea (10%), abdominal pain (5%), or hives (1%). The 1-year cost of managing lansoprazole failure in 195 patients was $61 690. However, the savings to the VA during the same time period, which totalled $321 360, more than offset the costs associated with the conversion.Lansoprazole intolerance requiring omeprazole conversion occurred in 5% of veterans on proton pump inhibitor therapy for chronic gastro-oesophageal reflux disease (GERD) symptoms and in 10% of patients with prior omeprazole success. The VA realized substantial cost savings in association with the formulary change.

Abstract

Due to certain risk factors that pertain to patients with spinal cord injury (SCI), the prevalence and severity of gastroesophageal reflux disease (GERD) may be greater among patients with SCI than the general population. In this retrospective study, the prevalence of GERD in patients with SCI as compared with age- and sex-matched controls, using pharmacy data from a large health care system, and the adequacy of the diagnostic evaluation process are evaluated and the symptom and disease severity in patients with SCI who were treated for GERD are assessed. The findings show a 22% prevalence of GERD in patients with SCI versus 28% in General Medicine Clinic controls. Although the symptom severity is similar in patients with SCI and controls, patients with SCI who have GERD symptoms undergo endoscopy less frequently. Disturbingly, the prevalence of severe, stage IV esophagitis among patients with SCI is higher than controls (p = .03). These results should alert clinicians caring for patients with SCI to more aggressively evaluate and treat such patients with reflux symptoms of heartburn and regurgitation before the development of complications.

Abstract

This article describes the use of gastric bypass surgery for severe gastroparesis in two lung transplant recipients. In addition to feeding intolerance, both our patients suffered from severe erosive esophagitis, transfusion-dependent upper GI hemorrhage, and recurrent aspiration pneumonia. They responded poorly to promotility agents and were eventually treated with Roux-en-Y esophagojejunostomy-one patient with subtotal gastrectomy, and one with gastric bypass without distal gastric resection. Both cases were improved by surgery. Early surgical referral may be indicated in the management of lung transplant recipients with severe symptomatic gastroparesis in whom medical management has failed. On the basis of our experience, gastric bypass with esophagojejunostomy is a worthwhile option in lung transplant recipients with severe gastroparesis.

Abstract

Barrett's esophagus (BE) results from chronic, severe gastroesophageal reflux and predisposes to esophageal adenocarcinoma. Cyclooxygenase (COX)-2 is involved in chronic inflammation and epithelial cell growth. We investigated COX-2 expression in BE and esophageal adenocarcinoma to explore a potential relation between COX-2 expression and metaplasia or carcinogenesis.Endoscopic mucosal biopsy specimens of Barrett's intestinal metaplasia (n = 30), Barrett's dysplasia (n = 11), and esophageal adenocarcinoma (n = 5) were compared with normal esophagus (n = 46) and duodenum (n = 46) and analyzed by Western blotting and immunohistochemistry.Immunoblots revealed constitutive expression of COX-2 in normal esophagus and duodenum. COX-2 protein expression was significantly higher in patients with Barrett's metaplasia, dysplasia, and adenocarcinoma compared with normal squamous esophageal or columnar duodenal epithelia and was heterogenous in different regions of the BE surface. Immunohistochemistry revealed prominent staining in the glands of BE, dysplasia, and adenocarcinoma and faint staining in the basal layers of squamous esophagus and the surface of the duodenum. In response to pulses of acid or bile salts in an ex vivo organ culture system, COX-2 expression increased significantly in BE tissues, and this effect was attenuated by the selective COX-2 inhibitor NS-398.The results show COX-2 expression in normal esophagus, which increases significantly in BE and esophageal adenocarcinoma. COX-2 is regulated ex vivo by exposure to acid or bile salts.

Abstract

Patients who have uncomplicated gastroesophageal-reflux disease (GERD) typically present with heartburn and acid regurgitation. We sought to determine the cost-effectiveness of H2-receptor antagonists (H2RAs) and proton-pump inhibitors (PPIs) as first-line empiric therapy for patients with typical symptoms of GERD.Decision analysis comparing costs and benefits of empirical treatment with H2RAs and PPIs for patients presenting with typical GERD was employed. The six treatment arms in the model were: 1) Lifestyle therapy, including antacids; 2) H2RA therapy, with endoscopy performed if no response to H2RAs; 3) Step up (H2RA-PPI) Arm: H2RA followed by PPI therapy in the case of symptomatic failure; 4) Step down arm: PPI therapy followed by H2RA if symptomatic response to PPI, and antacid therapy if response to H2RA therapy; 5) PPI-on-demand therapy: 8 wk of treatment for symptomatic recurrence, with no more than three courses per year; and 6) PPI-continuous therapy. Measurements were lifetime costs, quality-adjusted life years (QALYs) gained, and incremental cost effectiveness.Initial therapy with PPIs followed by on-demand therapy was the most cost-effective approach, with a cost-effectiveness ratio of $20,934 per QALY gained for patients with moderate to severe GERD symptoms, and $37,923 for patients with mild GERD symptoms. This therapy was also associated with the greatest gain in discounted QALYs. The PPI-on-demand strategy was more effective and less costly than the H2RA followed by PPI strategy or the other treatment arms. The results were not highly sensitive to cost of therapy, QALY adjustment from GERD symptoms, or the success rate of the lifestyle arm. However, when the success rate of the PPI-on-demand arm was < or =59%, the H2RA-PPI arm was the preferred strategy.For patients with moderate to severe symptoms of GERD, initial treatment with PPIs followed by on-demand therapy is a cost-effective approach.

Abstract

Maintenance of normal epithelial differentiation and proliferation is an important goal in cancer chemoprevention. Because acid has a dynamic effect on cell proliferation/differentiation of Barrett's esophagus (BE) ex vivo, we investigated the relationship between differentiation, proliferation, and dysplasia in BE biopsy specimens and explored the role of normalization of intraesophageal pH in altering the BE phenotype.Endoscopic biopsy specimens of BE (with or without dysplasia) were analyzed for (1) villin, a differentiation marker, by immunoblotting; (2) proliferating cell nuclear antigen (PCNA), a proliferation marker, by immunohistochemistry; and (3) dysplasia by histology before and after 6 months of normalization of intraesophageal pH (confirmed by 24-hour pH monitoring) with lansoprazole.At baseline, there was a negative correlation (r = -0.79) between villin and PCNA expression. Six months later, PCNA expression decreased and villin expression increased (P < 0.001) in 24 patients whose intraesophageal pH normalized. Fifteen patients had persistently pathological intraesophageal acid reflux and no change in villin or PCNA expression. There were no differences in the occurrence of dysplasia after 6 months in either group.In BE, there is an inverse relationship between villin and PCNA. In turn, dysplasia is unrelated to villin expression and well correlated with PCNA expression. Complete symptom eradication with lansoprazole does not guarantee normalization of intraesophageal pH profile in BE patients. Effective intraesophageal acid suppression favors differentiation and decreases proliferation. The intriguing possibility that acid suppression can be used to prevent dysplasia remains to be explored.

Abstract

Nonsteroidal antiinflammatory drugs (NSAID) are one of the most commonly used classes of medications worldwide. It is estimated that more than 30 million people take NSAID daily. Gastrointestinal (GI) complications related to NSAID therapy are the most prevalent category of adverse drug reactions. Patients with arthritis are among the most frequent users of NSAID and are therefore particularly at risk for these side effects. To evaluate the nature of NSAID-related GI complications and to determine how their frequency can be reduced, a series of studies of such complications in patients with rheumatic disease have been carried out based on data from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS). This report briefly reviews the literature and presents recent findings from the ARAMIS studies, which provide an update on published information. It addresses whether GI side effects such as dyspepsia can serve as warning symptoms for life-threatening GI complications and describes the risk factors for these events. It also summarizes a study that investigated whether H2-receptor antagonists and antacids affect the development of serious GI complications. In addition, ongoing research and topics to be addressed in future studies are described.

Abstract

The incidence of adenocarcinoma of the esophagus has been increasing in developing countries over the last three decades and probably reflects a genuine increase in the incidence of its recognized precursor lesion, Barrett's metaplasia. Despite advances in multimodality therapy, the prognosis for invasive esophageal adenocarcinoma is poor. An improved understanding of the molecular biology of this disease may allow improved diagnosis, therapy, and prognosis. We focus on recent developments in the molecular and cell biology of Barrett's metaplasia, a heterogeneous lesion affecting the transitional zone of the gastro-esophageal junction whose associated molecular alterations may vary both in nature and temporally. Early premalignant clones produce biological and genetic heterogeneity as seen by multiple p53 mutations, p16 mutations, aneuploidy, and abnormal methylation resulting in stepwise changes in differentiation, proliferation, and apoptosis, allowing disease progression under selective pressure. Abnormalities in expression of growth factors of the epidermal growth factor family and cell adhesion molecules, especially cadherin/catenin complexes, may occur early in invasion. Exploitation of these molecular events may lead to a more appropriate diagnosis and understanding of these lesions in the future.

Abstract

Acid produces a dynamic effect on the cell phenotype of Barrett's esophagus (BE) ex vivo. An acid pulse induces hyperproliferation, whereas continuous acid exposure promotes differentiation. To examine the mechanism for acid pulse-induced hyperproliferation, we studied the Na+/H+ exchanger (NHE), which plays a role in the control of intracellular pH and cell proliferation. NHE was inhibited pharmacologically in endoscopic BE biopsies using amiloride analogs. Cell proliferation was assessed after pulsed or continuous acid exposure using tritiated thymidine incorporation assays and immunohistochemical analysis of proliferating cell nuclear antigen expression. The NHE-dependent intracellular pH response to an acid pulse was examined by pH-sensitive microfluorimetry using a Barrett's adenocarcinoma cell line TE7. NHE inhibition significantly reduced the hyperproliferative acid-pulse effect. Furthermore, the acid-pulse activation of NHE occurred via increased transporter activity (22Na uptake) without any change in NHE-1 protein levels. Inhibition of protein kinase C (PKC), an NHE activator, also reduced the hyperproliferative response. The response of TE7 cells to an acid pulse was similar to that of BE biopsies in terms of cell proliferation and NHE and PKC dependence. Acid-pulse exposure of TE7 cells resulted in intracellular acidification followed by reneutralization to an intracellular pH greater than preacidosis values. We conclude that NHE may mediate the hyperproliferative response of BE to an acid pulse via changes in intracellular pH.

Abstract

Cold liquid ingestion may precipitate episodes of dysphagia and chest pain in patients with spastic esophageal motility disorders. The effect of hot liquids on esophageal symptoms, esophageal peristalsis, and clearance and any potential therapeutic benefit in such patients has not been examined. Using esophageal scintigraphy and manometry, we have investigated the effects of hot water swallows on dysphagia, chest pain, and esophageal motility and clearance in patients with esophageal motility disorders. We studied 48 men and women with intermittent dysphagia to both solids and liquids, chest pain, and/or regurgitation. All patients underwent upper endoscopy, barium swallow, and esophageal manometry using standard techniques. Esophageal scintigraphy assessed esophageal transit time (ETT) and retrograde intraesophageal movement of bolus at baseline (22 degrees C) and after hot (60 degrees C) water swallows. Esophageal manometry assessed the amplitude and duration of esophageal contractions in response to baseline and hot water swallows. Patients were followed clinically for as long as 6 months to assess symptomatic response. We found that baseline esophageal scintigraphy revealed a mean ETT of 48.5 seconds; after hot water swallow, mean ETT was 27.8 seconds (p < 0.001). The number of secondary peaks at baseline was 3.5; after hot water swallow, it was 2.1 (p < 0.001). Baseline esophageal manometry showed a mean esophageal body contraction amplitude of 188 mm Hg (mean duration, 11.8 seconds) in response to wet swallows and 125 mm Hg (mean duration, 5.7 seconds) with hot water swallows (p < 0.001). Clinically, 28 (58%) of 48 patients noted significant (>50%) improvement of their symptoms and have been ingesting hot water or other hot liquids regularly with their meals. We conclude that hot water accelerates esophageal clearance, decreases the amplitude and duration of esophageal body contractions, and improves symptoms in patients with esophageal motility disorders. Because of its safety and simplicity, it may have an important role in the management of these chronic conditions.

Abstract

Normalization of intraesophageal acid exposure is increasingly recognized as a desired goal in the management of Barrett's esophagus. In this prospective trial, we studied patients with Barrett's esophagus by 24-h intraesophageal pH monitoring after having completely eliminated their reflux symptoms with lansoprazole, to determine whether they had achieved normalization of intraesophageal pH.Thirty patients with Barrett's esophagus, all of whom had presented with reflux symptoms, were treated with lansoprazole (15-30 mg/day) until they were asymptomatic. Twenty-four-hour ambulatory pH monitoring was performed while they were receiving lansoprazole and were asymptomatic.Twelve patients (40%) showed persistent bipositional, pathologic acid reflux while on therapy, with a mean DeMeester score of 52.8 (95% CI: 33.8-71.8); the remaining 18 (60%) exhibited normalization of intraesophageal acid exposure with a score of 4.4 (95% CI: 2.3-6.6,p < 0.001). This inadequate control of intraesophageal pH is most likely due to incomplete gastric acid suppression induced by the drug and is associated with a variable acid (distal > proximal) exposure within the esophagus. The two groups were not different in regard to their symptom frequency and severity before therapy, amount of lansoprazole dosage required to eliminate symptoms, length of Barrett's metaplasia, presence of hiatal hernia, lower esophageal sphincter resting tone and length, or esophageal peristaltic function.Complete symptom eradication with lansoprazole (15-30 mg daily) in patients with Barrett's esophagus does not guarantee normalization of intraesophageal pH profile. If the goal of therapy in such patients is to achieve complete intraesophageal acid suppression, 24-h ambulatory esophageal pH monitoring should be performed to titrate therapy.

Abstract

Diseases of the oesophageal mucosa are particularly prevalent in the elderly population and may present with various symptoms, such as heartburn, dysphagia or chest pain. Recent technological advances, such as endoscopy, ambulatory pH monitoring and radiological imaging, have allowed for a more accurate diagnosis and assessment of disease severity. Depending on the leading presenting symptom, empirical medical therapy or stepwise diagnostic tests may be used. Elderly patients with mild reflux symptoms respond well to over-the-counter antacids, acid suppressants or prescription prokinetic drugs. Those with more severe gastrooesophageal reflux disease and Barrett's oesophagus benefit from powerful acid suppressive therapy to relieve symptoms, heal the mucosal damage and prevent complications. Long term, cost-effective pharmacological therapies are constantly being defined. Because of the widespread utilisation of medications in the elderly, drug-induced oesophageal injury should always be considered and prevented. An increasing number of immunocompromised elderly patients are diagnosed and successfully treated for infectious oesophagitis. Overall, for most elderly patients, when the diagnosis is made correctly, modern medical and/or surgical treatments yield maximal therapeutic benefit and improve quality of life.

Abstract

Barrett's esophagus, or specialized intestinal metaplasia, is a common condition associated with gastroesophageal reflux and an increased risk for adenocarcinoma of the esophagus and gastric cardia. Currently, clinical surveillance for early detection of adenocarcinoma relies on the histopathological assessment of dysplasia. In this review we present data from the published literature, and combine this with results from our own research, to address what is currently known about the environmental factors and the molecular changes thought to be important in the pathogenesis of Barrett's esophagus. The most important and well-characterized molecular changes, preceding the development of dysplasia, are alterations in the p53 and erbB-2 genes and aneuploidy. These molecular changes, as well as environmental influences, such as the quality and quantity of gastroduodenal refluxate, may result in abnormal cell proliferation which in turn promotes further genetic abnormalities and deregulation of cell growth. The identification of molecular changes, in the context of predisposing environmental factors, will enhance our understanding of the malignant progression of Barrett's esophagus leading to more effective surveillance and treatment.

Abstract

The perimenopausal and postmenopausal states are frequently accompanied by a variety of symptoms of hormonal imbalance. Although vasomotor, vaginal and genitourinary symptoms prevail, gastrointestinal complaints such as abdominal bloating may occur. In this study, we investigated the nature and prevalence of gastrointestinal and irritable bowel syndrome (IBS)-type complaints in women going through their climacteric and postmenopausal periods.228 women (170 postmenopausal and 58 premenopausal) who presented for evaluation at a primary care practice limited to women's health were evaluated prospectively by a previously validated gastrointestinal symptoms questionnaire designed to evaluate symptoms suggestive of IBS. At the time of their participation in the study, none of these women was presenting for evaluation of abdominal or genitourinary symptoms.Thirty-eight percent of postmenopausal women reported altered bowel function, in contrast to 14% of premenopausal ones (p < 0.001). Despite this, the two groups did not differ in regards to the occurrence of abdominal pain, diarrhea or constipation, suggestive of IBS. The prevalence of IBS-type complaints peaked to 36% during the climacteric period (40-49 years). Laxative usage (9.4% prevalence), gaseousness/excessive flatulence (48% prevalence) and heart-burn/acid regurgitation (34% prevalence) were also more common among postmenopausal women. Estrogen use did not affect gastrointestinal symptoms in any of the two groups.Although the possible role of aging on symptom perception-regardless of hormonal status-cannot be ruled out, these results suggest that peri- and postmenopausal women have a high prevalence of altered bowel function and IBS-like gastrointestinal complaints that should be carefully assessed. If the diagnosis of IBS is confirmed, appropriate treatment may improve patients' symptoms, although this approach requires further study.

Abstract

Current serological tests for Helicobacter pylori (HP) infection are not useful in assessing active infection or eradication. The feasibility, sensitivity, and specificity of serum 13C-bicarbonate (13C-HCO3) measurement in determining gastric HP before and after eradication by antibiotics were investigated.Twenty-seven symptomatic patients underwent endoscopy, biopsy, and CLOtest. Patients then consumed a 13C-urea-rich meal; serum was collected before and 1 hour after meal ingestion for quantitative determination of 13C by mass spectrometry. Postprandial fractional elevation of 13C (delta 13C-HCO3) was correlated with endoscopy, histology, and CLOtest at baseline and at 4 and 8 weeks after therapy.delta 13C-HCO3 +/- SEM was 17.02 +/- 2.94 in HP-positive patients and 2.77 +/- 044 in HP-negative patients (P < 0.0001). In HP-positive patients who responded to therapy, the mean change was initially 20.5 +/- 3.1, 3.2 +/- 0.9 1 month after therapy, and 2.8 +/- 0.4 2 months after therapy (P < 0.001). The overall sensitivity of this method was 90.6% (95% confidence interval, 74.9-98.0), and its specificity was 85.7% (95% confidence interval, 42.1%-99.6%). delta 13C-HCO3 correlated positively with the degree of histological gastritis and the number of HP organisms.Serum 13C-HCO3 analysis is a novel, simple, and noninvasive method for diagnosis and assessment of eradication of HP infection.

Abstract

Cell proliferation and differentiation are influenced by environmental factors, including the extracellular pH. We recently showed, using an ex vivo organ culture system of human mucosal Barrett's esophageal biopsies, that acid has a highly variable effect on cell proliferation and differentiation depending on the pattern of acid exposure. Study of the mechanisms underlying these dynamic effects of acid on this premalignant intestinal-like epithelium is hampered by lack of an immortalized cell line. We therefore investigated the effect of acid exposure on the human colonic carcinoma cell line HT29, chosen because of its intestinal cell derivation and its ability to differentiate in vitro. HT29 cells exposed to pH 5 medium either continuously (up to 3 weeks), or as a short (1 hour) pulse, were compared with cells cultured at pH 7.4. Villin expression was induced only by long term acid exposure, and correlated with the development of differentiated polarized cells that contain a brush border and microvillus inclusions. Chronic acid exposure arrested cell proliferation, whereas a 1 hour acid-pulse enhanced cell proliferation, as determined by [3H]thymidine incorporation assays and proliferating cell nuclear antigen expression. Serum starvation attenuated the hyperproliferative effect of an acid-pulse. In addition, the doubling time of at least the first cell cycle after an acid-pulse was shortened. The Na/H exchanger is likely to play a role since the hyperproliferative acid-induced response was blocked by amiloride; and the activity of the exchanger was increased at acidic pH as determined by 22Na uptake. These results support a role for extracellular pH on cell proliferation and differentiation of HT29 cells. Furthermore, these findings parallel the dynamic effects of acid on Barrett's esophagus, and suggest that HT29 cells could serve as an in vitro model for studying the mechanism of acid modulation in Barrett's esophagus.

Abstract

This study was performed to review information on functional and anatomic esophageal manifestations in patients with rheumatic disorders and to outline their pathogenesis, diagnosis, and treatment in light of the current medical, endoscopic, and surgical advances. A MEDLINE search of English-language articles published between 1985 and 1995, reviews of the bibliographies of textbooks, and a manual search of the reference lists of relevant articles formed the data sources, all combined with our own clinical experience. Primary research and review articles addressing the pathogenesis, diagnosis, treatment, prognosis, and complications of esophageal disease occurring in a rheumatic context were selected, with emphasis on recently developed medical, endoscopic, and surgical methods for diagnosis and management. Study design and quality were assessed, with particular attention paid to methods and aims. Relevant data on frequency, clinical presentation, and relationship to underlying rheumatic disorder, prognosis, and clinical management were analyzed. Esophageal manifestations are common in patients with rheumatic diseases and range in nature and severity from functional myopathic or neuropathic esophageal dysmotility to extrinsic lumenal compression and esophageal mucosal damage from gastroesophageal acid reflux or opportunistic infection. The primary symptoms of heartburn, dysphagia, odynophagia, chest pain, and bleeding may be directly related to the underlying rheumatic disease or may be the unwanted effects of therapy with nonsteroidal antiinflammatory drugs, immunosuppressants, or disease-modifying agents. Easily over-looked in the context of a multisystemic disease, these esophageal symptoms may be amenable to simple treatments, but frequently require a thorough assessment by modern, sophisticated diagnostic tools. In many instances, functional and structural involvement of the esophagus in patients with rheumatic disorders requires a high index of suspicion for an early diagnosis, correct assessment, intensive surveillance, and aggressive therapy to avoid end-organ damage and decline in quality of life. Significant recent advances in the understanding of esophageal pathophysiology, the development of diagnostic techniques, progress in diagnostic and therapeutic endoscopy, and minimally invasive surgery allow early detection and effective long-term therapy for esophageal dysfunction associated with rheumatic diseases.

Abstract

The neoplastic progression of Barrett's esophagus (BE) may involve genomic instability, inactivation of tumor suppressor genes, or activation of oncogenes. Because activation of Src tyrosine kinase occurs in malignant and premalignant epithelia of the colon, the aim of this study was to determine whether BE is associated with changes in Src expression and activity.Src expression and in vitro protein-tyrosine kinase activity in endoscopic tissue samples of BE and esophageal adenocarcinoma were measured and compared with expression and activity in normal esophagus and duodenum from the same patient. Src phosphorylation was assessed by immunoblotting using antiphosphotyrosine antibodies and two-dimensional tryptic phosphopeptide mapping.Src-specific activity was 3-4 fold higher in BE and 6-fold higher in esophageal adenocarcinoma than in control tissues. Different regions of BE from the same patient showed heterogeneity in Src activity compared with the uniform Src activity observed in different regions of normal esophagus and duodenum. In all tissues, Src kinase activity and protein were associated preferentially with the Triton X-100-soluble rather than-insoluble fraction. Immunoblotting and two-dimensional tryptic phosphopeptide mapping showed dephosphorylation of Src at Tyr527 in BE.Src is activated in BE, in part, because of dephosphorylation of Tyr527. Src activation and its heterogeneous expression occur before development of dysplasia or carcinoma in BE.

Abstract

Barrett's esophagus (BE), or specialized intestinal metaplasia, is a premalignant heterogeneous epithelium associated with reflux and an increased risk for adenocarcinoma. Since acid is a major component of refluxate, we investigated its effects ex vivo on cell differentiation as determined by villin expression; and on cell proliferation, as determined by tritiated thymidine incorporation and proliferating cell nuclear antigen expression. To mimic known physiological conditions, endoscopic biopsies of normal esophagus, BE, and duodenum were exposed, in organ culture, to acidified media (pH 3-5) either continuously, or as a 1-h pulse and compared with exposure to pH 7.4 for up to 24 h. Before culture, villin expression was noted in 25% of BE samples, and increased after 6 or 24 h of continuous acid to 50% or 83% of BE samples, respectively. Increased villin expression correlated with ultrastructural maturation of the brush border. In contrast, an acid-pulse followed by culture at pH 7.4, did not alter villin expression in BE. Moreover, continuous acid exposure blocked cell proliferation in BE, whereas, an acid-pulse enhanced cell proliferation, as compared to pH 7.4. Based on our ex vivo findings, we propose a model in which the diverse patterns of acid exposure in vivo may contribute to the observed heterogeneity and unpredictable progression to neoplasia of BE.

Abstract

Diffuse esophageal spasm (DES) is a motor disorder of the esophageal smooth muscle characterized by multiple spontaneous contractions and by swallow-induced contractions that are of simultaneous onset, large amplitude, long duration, and repetitive occurrence. Although the pathogenesis of DES is unknown, provocative studies with cholinergic stimulation, esophageal balloon distention, or acid instillation have suggested involvement of both sensory and motor mechanisms. This report describes a patient with DES who would predictably become symptomatic with dysphagia and chest pain upon inhalation of perfume or other strong odors. Using esophageal scintigraphy to quantitate and analyze esophageal transit in this patient, we report for the first time that olfactory stimulation triggers episodes of DES and that such phenomena are mediated through the vagus nerve, because they can be ameliorated by the administration of ipratropium bromide. These observations suggest a new (sensory) pathway for the induction of DES and raise the intriguing possibility that inhaled anticholinergics may have a therapeutic role in the management of spastic esophageal motility disorders.

Abstract

Barrett's esophagus (BE) is a metaplastic change of the squamous esophageal epithelium to columnar gastric or intestinal-like epithelium. BE is associated with long-standing gastroesophageal reflux disease and carries an increased risk for dysplasia and adenocarcinoma. Little if any is known regarding the differentiation state of esophageal metaplasia and its relationship to carcinogenesis. In this study, we investigated the potential of villin, a cytoskeletal protein, and Ep-CAM, a glandular epithelial glycoprotein, to serve as markers for enterocytic differentiation in BE at the molecular level. Endoscopic mucosal biopsy samples of normal esophagus, BE, stomach and duodenum were collected from 23 patients with BE. Biopsies were analyzed for villin and Ep-CAM expression by immunoblotting, and in some cases for the presence of microvilli by electron microscopy. By mapping of BE segments in 6 patients, correlations were also made between the histologic evidence of metaplasia and villin expression. Villin was uniformly expressed in all duodenal samples but was not detected in normal esophagus and stomach. In BE biopsies, villin expression was limited to the subset of patients whose adjacent biopsies showed microvilli by electron microscopy. In several patients studied, however, the expression of villin and the epithelial glycoprotein Ep-CAM differed among various regions of esophageal metaplasia within the same patient. Mapping studies failed to reveal any correlation among histologic evidence of metaplasia, dysplasia and villin expression and confirmed the multifocal heterogeneity of villin expression in BE. Preliminary data of 4 adenocarcinoma patients studied showed that villin expression was absent in 3 and very low in 1 patient. Ep-CAM was highly expressed in all adenocarcinoma patients. Our results show that BE represents a complex epithelium with significant heterogeneity in antigen expression and ultrastructural morphologic features. This molecular heterogeneity supports the presence of different stages of differentiation within the same epithelium.

Abstract

To compare ranitidine to misoprostol with respect to the prevention of gastric and duodenal ulcers in patients on chronic NSAID therapy.A multi-center, 8-wk, randomized, double-blind study. Eligible patients were on chronic NSAID therapy and were experiencing NSAID-related upper gastrointestinal (UGI) pain without UGI endoscopic evidence of gastric or duodenal ulcers. Patients enrolled in the study were randomized to either misoprostol 200 micrograms q.i.d. or ranitidine 150 mg b.i.d.. Follow-up UGI endoscopy was performed after 4 and 8 wk of treatment. Therapeutic failure was considered the development of a gastric or duodenal ulcer > or = 0.3 cm in diameter with perceptible depth.Gastric ulcers were found in only 1/180 (0.56%) patient on misoprostol and in 11/194 (5.67%) patients on ranitidine, a difference that was statistically significant (p < 0.01). Duodenal ulcer rates were similar for the ranitidine (2/185 or 1.08%) and misoprostol (2/181 or 1.10%) groups.Misoprostol is significantly more effective than ranitidine in the prevention of NSAID-induced gastric ulcers. Ranitidine was as effective as misoprostol for the prevention of NSAID-induced duodenal ulcers. Misoprostol should be used for prophylaxis against both gastric and duodenal ulceration in patients on chronic NSAID therapy.

Abstract

Cadherins are cell adhesion molecules that are thought to play a vital role in cell-cell adhesion; loss or down-regulation of their expression has been implicated in neoplasia. Barrett's esophageal columnar metaplasia (BE) is a premalignant lesion for esophageal adenocarcinoma with clinical symptoms similar to those of gastroesophageal reflux disease and esophagitis. In this study, we investigated the potential relationship between E-cadherin expression and inflammation, metaplasia, and carcinogenesis in esophagitis, BE, and esophageal adenocarcinoma.Endoscopically obtained mucosal biopsy specimens of esophagitis (n = 6), BE with or without dysplasia (n = 16), and esophageal adenocarcinoma (n = 6) were analyzed for the expression of E-cadherin by both Western analysis and immunoperoxidase staining.Densitometric analysis of Western blots revealed the expression of E-cadherin to be significantly lower in patients with BE compared with normal esophageal epithelium, regardless of the presence or absence of dysplasia (p < 0.03). No significant differences were noticed between the normal esophagus and the esophagitis groups. In the adenocarcinoma group, one patient showed complete loss of E-cadherin expression, and the other five patients showed significantly reduced expression that was even lower than that in BE (p < 0.01). Immunoperoxidase staining matched the Western analysis results.We conclude that loss of or reduced E-cadherin expression may play a role in the progression of BE to adenocarcinoma.

Abstract

An 81-year-old man with a 3-year history of dysphagia underwent endoscopic resection of a 1-cm-diameter distal esophageal mass. Examination revealed a submucosal neoplasm with a circumscribed growth pattern composed of tubules, cysts, and papillae in association with a marked interstitial lymphoid infiltrate. The cyst lumens and papillae were lined by two to six layers of cytologically bland cuboidal to columnar cells with rare mitotic figures. The basal layer of cells was uniformly positive for smooth-muscle actin. Mucin-positive intracytoplasmic lumens were focally present, but cytoplasmic mucin was not seen. There was no evidence of Barrett's metaplastic epithelium. These features are similar to those in two, possibly three, previously reported cases of esophageal adenomas and bear a resemblance to sialadenoma papilliferum, a rare neoplasm of the minor salivary glands. Their clinicopathologic and immunohistologic features suggest that these neoplasms derive from the submucosal gland ducts. Comparison with the previously reported cases indicates that although the proportions of the various components (tubules, cysts, and papillae) may vary, all cases appear to pursue a slowly growing, clinically indolent course with no evidence of recurrence after complete resection.

Abstract

Colonic lymphoid nodules, also known as focal colonic lymphoid hyperplasia, have been previously described either as an indication of disease or as a normal variant in adults, with current opinion favoring the latter. The finding of isolated or confluent colonic lymphoid nodules on colonoscopy may nevertheless cause confusion with other endoscopic diagnoses.In this study, we describe new endoscopic features of colonic lymphoid nodules, and we correlate them with other clinical and histopathological characteristics. Our experience is based on thorough evaluation of 13 cases of colonic lymphoid nodules that were consecutively observed during colonoscopy over the past 2 yr.Colonic lymphoid nodules may appear as red macules, as circumferential target lesions (halo sign), or as raised papules; they occur in both men and women, predominantly affect the rectum, and appear to be of no clinical significance. Histologically, colonic lymphoid nodules may involve the mucosa or the submucosa, in the form of either lymphoid aggregates or lymphatic nodules.With the widespread use of video colonoscopy, the macular or papular endoscopic characteristics of colonic lymphoid nodules should be increasingly recognized, confirmed histologically, and distinguished from other pathological lesions. Improved endoscopic recognition will allow the potential association of colonic lymphoid nodules with other colonic pathology to be eventually elucidated.

Abstract

To determine the efficacy of misoprostol for the prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced duodenal and gastric ulcers in arthritis patients receiving NSAID therapy.A randomized, double-blind, multicenter, placebo-controlled trial.Six hundred thirty-eight private, Veterans Affairs, health maintenance, and academic practices.Six hundred thirty-eight patients with chronic inflammatory or noninflammatory arthritis who were taking an NSAID but who did not have a gastric or duodenal ulcer on screening endoscopy received treatment with ibuprofen, piroxicam, naproxen, sulindac, tolmetin, indomethacin, or diclofenac daily for 3 months. Four hundred fifty-five (71%) patients completed the trial.Patients meeting the entry criteria were randomized to receive either misoprostol, 200 micrograms, or placebo, four times a day for 12 weeks.The endoscopy was repeated at 4, 8, and 12 weeks. The development of a duodenal or gastric ulcer (defined as a circumscribed mucosal defect > or = 0.5 cm in diameter and with perceptible depth) was regarded as prophylactic failure.By 12 weeks, a duodenal ulcer developed in 2 of 320 (0.6%; 95% CI, 0.2% to 3.9%) patients randomized to receive misoprostol, compared with 15 of 323 (4.6%; CI, 2.8% to 8%) patients receiving placebo (P = 0.002). A gastric ulcer developed in 6 of 320 (1.9%; (CI, 0.8% to 4.4%) patients, compared with in 25 of 323 (7.7%; CI, 5.1% to 11.4%), respectively.Misoprostol significantly lowers the frequency of both duodenal and gastric ulcer development in patients who require long-term therapy with NSAIDS.

Abstract

Noninvasive detection of Helicobacter pylori (HP) requires serum or salivary antibody testing or the CO2 breath test. Since gastric HP produces a potent urease, a meal rich in 13C-labeled urea should lead to a measurable quantity of isotopic CO2 in the serum. This study investigates the feasibility, sensitivity, specificity, and potential of the measurement of serum 13C-bicarbonate (13CHCO3) in determining the presence of gastric HP. Nineteen patients with upper gastrointestinal symptoms assessed by intensity-duration questionnaire underwent endoscopy and biopsies for histology, Giemsa stain, and urease activity testing by CLOtest. Patients also consumed a 13C-urea-rich meal (5 mg/kg body weight, 99% 13C, MSD Isotopes, Montreal Canada). Serum was collected every 30 min for 3 h for quantitative determination of 13C by mass spectrometry. Fractional elevation of 13C after the enriched meal was then correlated with endoscopy, histology, and CLOtest. Fourteen of the 19 patients studied had histologic evidence of gastritis; 11 of 19 had positive CLOtest and had HP by histology and Giemsa stain. All HP-positive patients had significant elevation of 13CHCO3, compared with HP-negative patients. The mean maximum absolute change from baseline was 15.3 delta 13CHCO3 (range, 6.7-29.9) and occurred from 15 to 90 min; 13CHCO3 in HP-negative patients was significantly less (p < 0.05) than HP-positive patients with a mean value of 2.3 delta 13CHCO3 (range, 0-5.3). We conclude that serum 13CHCO3 analysis accurately reflects HP gastritis. This novel method is noninvasive, less labor intensive, less time consuming, and may have a value as a diagnostic screening tool for humans or in the assessment of the results of therapy in patients with HP infection.

Abstract

Elderly patients are at high risk for developing diarrhea and colitis as a complication of antimicrobial therapy. Clostridium difficile, the causative agent of antibiotic-associated diarrhea and colitis produces an enterotoxin (toxin A) and a cytotoxin (toxin B). Of these two exotoxins, toxin A appears to be largely responsible for the inflammatory phenomena of C. difficile colitis, because it produces secretion, pronounced granulocytic infiltration, and epithelial cell necrosis and ulceration in ligated ileal loops of experimental animals. We have recently demonstrated that the inflammatory effects of C. difficile toxin A in the intestine may be related to its ability to mobilize intracellular calcium and elicit a chemotactic response by human granulocytes. In this study, in order to explain why the elderly are at greater risk for developing antibiotic-associated colitis, we investigated the effects of toxin A on activation of granulocytes from healthy elderly and young subjects. Highly purified toxin A and the chemotactic factor N-formyl-Met-Leu-Phe (FMLP) at concentrations of 10(-7) M both elicited a significant (p less than 0.001) and comparable chemotactic and chemokinetic response in human granulocytes from both age groups. A significantly (p less than 0.001) increased chemotactic effect in elderly subjects compared with young subjects was elicited by toxin A and not by FMLP. These findings suggest that the enhanced intestinal inflammatory effects of C. difficile in the elderly, compared with the young, may be related to the ability of its enterotoxin to elicit a more pronounced chemotactic response by granulocytes.

Abstract

Fibromyalgia and irritable bowel syndrome frequently coexist. In this study, we utilized a previously validated self-administered questionnaire to assess the prevalence of symptoms of bowel dysfunction and irritable bowel syndrome in 123 patients with fibromyalgia as compared to 54 patients with degenerative joint disease (DJD) and 46 normal controls. Ninety (73%) of the fibromyalgia patients reported altered bowel function as compared to 20 (37%) DJD patients and none of the normal controls (P less than 0.001). Ninety-nine patients (81%) reported normal alternating with irregular bowel pattern, and 77 (63%) had alternating diarrhea and constipation. In contrast, only 24 (44%) of DJD patients and six (13%) of controls had regular alternating with irregular bowel pattern and only 12 (22%) of the DJD patients and none of the healthy controls had alternating constipation and diarrhea (P less than 0.01). Other bowel dysfunction complaints noted in the fibromyalgia group were abdominal gas (59%), nausea (21%), diarrhea (9%), and constipation (12%). Seventy-nine (64%) fibromyalgia patients reported frequent abdominal pain that was stress-related 47% of the time. Laxative use was frequent in the fibromyalgia group (19%) and absent in the other two groups. Fifty percent of fibromyalgia patients, compared to 28% of DJD patients, felt that their bowel complaints were worse during exacerbations of their joint disease (P less than 0.05). In conclusion, patients with fibromyalgia have a high prevalence of gastrointestinal complaints that should be carefully assessed. If the diagnosis of IBS is confirmed, appropriate treatment may improve patients' symptoms, although this approach requires further study.

Abstract

The purpose of this study was to compare the effects of Clostridium difficile toxin A and cholera toxin on fluid secretion, intestinal permeability, and arachidonate metabolites in rabbit ileum. Injection of 25 micrograms of either purified toxin into 10-cm ileal loops caused significant increases in fluid secretion and intestinal permeability to mannitol as well as release of prostaglandin E2 into the lumen. Toxin A, but not cholera toxin, caused a severe inflammatory reaction of the lamina propria and necrosis of enterocytes as well as increased release of leukotriene B4. The toxin A-mediated increases in prostaglandin E2 and leukotriene B4 could be blocked by prior instillation of 10 mg of 5-aminosalicylic acid into ileal loops. 5-Aminosalicylic acid also significantly diminished the expected increase in mannitol permeability after both toxins, but had no significant inhibitory effect on fluid secretion or, in the case of toxin A, intestinal inflammation. Our results indicate that C. difficile and cholera enterotoxins differ substantially in their effects on the rabbit intestine. Clostridium difficile toxin A, an inflammatory toxin, produces a striking infiltration of the lamina propria with neutrophils that is associated with increased release of leukotriene B4. In contrast, cholera toxin does not cause inflammation or leukotriene B4 release. Increased release of prostaglandin E2 occurs after exposure to both toxins and appears to be correlated with increased intestinal permeability.

Abstract

In these studies we determined the effects of purified Clostridium difficile toxin A, an enterotoxin, on the electrophysiological and contractile properties of rabbit intestinal circular smooth muscle and correlated these effects with changes of smooth muscle morphology. Simultaneous measurements of intracellular membrane potential and contractility were determined in excised ileal muscle strips after administration of toxin A in vivo (60 micrograms/ml) into an isolated rabbit ileal loop or directly in vitro (0.1-60 micrograms/ml) to a normal muscle strip. Toxin A injection in vivo resulted in membrane depolarization and increased slow wave and action potential frequency. Toxin A injection in vivo also caused increased amplitude of spontaneous and carbachol-induced phasic contractions. The electrophysiological effects of in vivo administration of toxin A were correlated with an inflammatory infiltrate of the lamina propria, but no light or electron microscopic evidence of injury to smooth muscle cells was seen. In contrast to the in vivo studies, direct in vitro exposure of normal ileal muscle strips to toxin A had no effect on either spontaneous or carbachol-induced electromechanical activity. Our results indicate that in vivo administration of C. difficile toxin A into a rabbit ileal loop, but not direct in vitro exposure, causes significant alterations of smooth muscle excitation-contraction coupling that may be mediated by products of local inflammatory cells.

Abstract

Clostridium difficile, a common enteric pathogen, mediates tissue damage and intestinal fluid secretion by release of two protein exotoxins: toxin A, an enterotoxin, and toxin B, a cytotoxin. Because toxin A elicits an intense inflammatory reaction in vivo, we studied the effects of highly purified C. difficile toxins on activation of human granulocytes. Toxin A at concentrations of 10(-7) to 10(-6) M, but not toxin B, elicited a significant chemotactic and chemokinetic response by granulocytes that was comparable with that induced by the chemotactic factor N-FMLP (10(-7) M). Neither toxin stimulated release of superoxide anion from granulocytes. Toxin A produced a rapid, transient rise in cytosolic [Ca2+]i, as measured by quin 2 fluorescence. Pertussis toxin and depletion of intra- and extracellular calcium blocked the toxin A effect on cytosolic [Ca2+]i. These findings suggest that the inflammatory effects of C. difficile toxin A in the intestine may be related to its ability to mobilize intracellular Ca2+ and elicit a chemotactic response by granulocytes.

Abstract

The pathogenesis of Clostridium difficile enterocolitis appears to involve colonization of the bowel followed by release of toxin A, an enterotoxin, and toxin B, a cytotoxin. The purpose of this study was to determine the effect of purified toxins A and B on intestinal secretion, epithelial permeability, and morphology in perfused rabbit ileal loops. Intestinal permeability after toxin exposure was assessed by blood-to-lumen clearance of [3H]mannitol. Toxin A at doses of 5-100 micrograms/10 cm ileal loop caused a threefold to fivefold increase in [3H]mannitol permeability (p less than 0.001) vs. equal concentrations of toxin B or buffer control. In addition, perfusate from toxin A-exposed loops contained significantly more neutrophils (p less than 0.001) than toxin B or control loops. Toxin A caused severe epithelial cell necrosis with destruction of villi and polymorphonuclear infiltration. Electron microscopy of mucosa subjected to a low dose of toxin revealed widespread nonspecific dilatation of endoplasmic reticulum and mitochondrial swelling. In contrast to these effects of toxin A in ileal loops, in vitro experiments with ileal explants in short-term organ culture revealed that toxin A had no effect on epithelial cell permeability, protein synthesis, release of alkaline phosphatase, or morphology. Our results show that purified toxin A but not toxin B causes severe inflammatory enteritis in rabbit ileal loops, but has no discernable effect on rabbit ileum in vitro. We speculate that toxin A may contribute significantly to intestinal damage in C. difficile-associated colitis and diarrhea.

Abstract

The pathophysiology of Clostridium difficile colitis is thought to be mediated by release of toxin A, an enterotoxin, and toxin B, a cytotoxin. We compared the differential effects of toxin B on protein synthesis in IMR-90 fibroblasts and in hamster esophagus, stomach, gallbladder, small intestine, and cecum in organ culture. Toxin B in low concentrations stimulated (p less than 0.001) incorporation of [3H]leucine into fibroblast proteins, whereas at higher dosages it inhibited incorporation (p less than 0.001). This biphasic effect was independent of cell rounding and was not caused by a change in uptake of precursor. Purified toxin B had no effect on protein synthesis in a cell-free rabbit reticulocyte translation system, indicating that inhibition of protein synthesis in intact fibroblast monolayers and intestinal explants is a consequence of toxin B effect on some other cellular target. Toxin B significantly inhibited protein synthesis in hamster cecal explants in a dose-dependent fashion. Again, this inhibition was not mediated by altered precursor uptake. Toxin B significantly inhibited in vitro protein synthesis in hamster terminal ileum, cecum, and sigmoid colon, but not in esophagus, gallbladder, stomach, or duodenum. These results suggest that toxin B-mediated inhibition of protein synthesis may be a generalized toxic effect in tissue culture cells and intestinal epithelium. Inhibition of protein synthesis in the distal intestinal epithelium may contribute to the pathophysiology of colitis caused by this organism.